Pre-test Probability FOCUS and D-dimer for Acute Aortic Syndromes

  • STATUS
    Recruiting
  • End date
    Dec 1, 2022
  • participants needed
    1700
  • sponsor
    Azienda Ospedaliero-Universitaria Careggi
Updated on 31 July 2021

Summary

Observational, prospective, multicentre, international, non-profit, investigator-driven, diagnostic accuracy study performed in several international EDs. The aim of the study will be to evaluate the performance of an integrated algorithm based on aortic dissection risk score, focus cardiac ultrasound and D-dimer to rule-in and -out acute aortic syndromes. The final diagnosis will be established after review all available hospital clinical data and one month follow-up.

Description

Background and rationale

Acute aortic syndromes (AASs) are deadly and difficult to diagnose cardiovascular emergencies. AASs include acute aortic dissection, intramural aortic hematoma, penetrating aortic ulcer and spontaneous aortic rupture. A conclusive diagnosis of AASs requires an advanced imaging exam, such as computed tomographic angiography (CTA), transoesophageal echocardiography (TEE) or magnetic resonance imaging. These exams are time-consuming, costly and frequently require transfer of patients to specialized clinical centres. CTA, the most frequently used advanced imaging exam for suspected AASs in the Emergency Department (ED), exposes patients to significant ionizing radiations and to contrast medium, carrying inherent risks of anaphylaxis and contrast nephropathy. Selection of patients necessitating an advanced aortic imaging exam is therefore worrisome. There is a need for standardized diagnostic management of AAS workup, and in particular for a validated diagnostic algorithm incorporating evidence-based decision rules allowing:

  1. rapid identification of patients necessitating urgent CTA;
  2. safe rule-out of patients not requiring CTA. Based on available guidelines and further evidence, standardized decision rules for rule-in and rule-out of AASs should be effectively based on: (1) standardized pre-test probability assessment, (2) bedside imaging of the aorta with focus cardiac ultrasound (FOCUS) and (3) biomarker testing (D-dimer assay).

Aim of the study The aim of the present study will be to evaluate the performance of an integrated algorithm for standardized diagnostic workup (rule-in, rule-out) of suspected AASs.

Setting This observational multicentric diagnostic accuracy study will be performed in the setting of several international EDs. Participating EDs will satisfy the following criteria for 24 hours / 7 days, in their routine clinical practice: (1) experienced use of bedside FoCUS, (2) local access to urgent D-dimer (DD) assay, (3) local access to urgent CTA. Both hub and spoke centers will be allowed to participate in the study, if local census is >30.000 visits/years.

Study design

This will be an observational, prospective, multicentre, international, non-profit, investigator-driven, diagnostic accuracy study. The study protocol does not imply any modification in the routine diagnostic and therapeutic approach to patients with suspected AASs. The only difference from standard care will be:

  1. registration of selected demographic and clinical data of study patients, obtained during the index ED visit;
  2. follow-up (by telephone or clinical visit) of patients after 1 month from the index ED visit, for collection of selected clinical data.

Study population The study will be performed on consecutive adult outpatients evaluated for specified symptoms in the ED, in whom AASs are considered in differential diagnosis by the attending physician(s). Eligibility will be defined during or after medical evaluation in the ED and always before establishment of a final diagnosis. In each centre, patient recruitment will start after obtaining approval from the local Ethic Committee.

Study methods and organization Patients will be evaluated in the ED by an authorized physician practicing Emergency Medicine and will be managed in accordance with international guidelines. The recommended standard of care for diagnosis and treatment of patients with suspected AAS will be as indicated by the European Society of Cardiology 2014 guidelines. However, attending physicians will be allowed to derogate from guideline indications based on the clinical scenario, irrespective of patient's participation to the present study. After medical evaluation a clinical suspicion of AAS will prompt to possible enrolment in the study. The attending physician or an authorized study research investigator/collaborator will then acquire patient (or next of kin, if deemed necessary) consent to participate to the study and will fill a standardized clinical form reporting the relevant clinical data.

Aortic dissection detection risk score The aortic detection dissection- risk score (ADD-RS) will be calculated based on the number of categories where at least one risk marker is present. Patients will be classified at low probability of AAS, if ADD-RS 1 (at least 1 risk marker present, in no more than 1 risk category), or at high probability of AAS if ADD-RS >1 (at least 1 risk marker present, in more than 1 risk category).

D-dimer DD levels will be analysed in the hospital laboratory on venous samples with an automated test. Diagnostic tests will be site-specific. DD is defined negative if lower than 500 ng/ml (Fibrinogen Equivalent Unit, FEU). This cut off has been validated for the diagnosis of AAS in previous studies.

Focused cardiac ultrasound The attending physician, a cardiologist or an authorized study research investigator expert in bedside emergency ultrasonography will perform a FoCUS on study patients during ED evaluation, before advanced aortic imaging tests or surgery. Evaluation of the heart and aorta will be performed with the patient in the supine or left lateral decubitus positions, using the following views: (1) left parasternal (long-axis) and (2) suprasternal notch view. Additional views including apical, subcostal, right parasternal, abdominal and neck for carotid arteries will be decided by the attending physician.

The following will be considered as direct sonographic signs of AASs:

  1. presence of an intimal flap separating two aortic lumens;
  2. presence of an intramural aortic thickening (circular or crescentic thickening of the aortic wall >5 mm);
  3. presence of a crater-like outpouching with jagged edges in the aortic wall.

The following signs will also be researched, as potential indirect sonographic signs of AASs:

  1. thoracic aorta dilatation (diameter 4 cm);
  2. pericardial effusion or tamponade
  3. aortic valve regurgitation at colour Doppler (at least moderate), based on subjective evaluation.

Advanced Aortic imaging The advanced aortic imaging exam used to confirm or refuse a diagnosis of AASs will be CTA, TEE or magnetic resonance angiography, performed by physicians not involved in the present study, according to local procedures. Patient enrolment in the study will not change standard patient management and will not affect medical decision to perform aortic imaging. Instruments used for imaging will be site-specific. These exams will be performed and interpreted by specialized radiologists, cardiologists or surgeons not involved in the present study.

Follow-up data AASs are difficult to diagnose disease entities. Given the severity of AASs in untreated patients, investigators assume that individuals with an undiagnosed AAS would experience major clinical events leading to conclusive diagnosis within 30 days from the ED visit. Therefore, all study patients will enter a 30-day clinical follow-up to allow accurate case adjudication.

Final diagnosis The final diagnosis will be established in each centre dichotomically (presence or absence of an AAS) by two senior investigators, who will review all available clinical data (including aortic imaging studies, medical, surgical, autopsy records if applicable). Reviewers will be blinded to: ADD-RS risk score stratification, FoCUS findings and D-dimer levels. The reviewers will judge on presence or absence of an AAS, and defined the AAS type: acute aortic dissection, aortic intramural hematoma, penetrating aortic ulcer or spontaneous aortic rupture, and Stanford classification.

Analysis and statistical methods Dichotomous data will be expressed as proportions and continuous data as mean and standard deviation (SD). Pearson's chi square test will be used for the comparison of dichotomous data, and the unpaired Student's t-test will be used to compare normally distributed data. The diagnostic performance of D-dimer will be assessed by computing sensitivity, specificity, negative and positive predictive values and negative and positive likelihood ratios with their 95% confident interval (95% CI) in all patients. The failure rate (or false negative proportion) will be calculated as the number of patients with a final diagnosis of AAS divided by the number of patients satisfying rule-out criteria. The rule-out efficiency will be calculated as the number of patients satisfying the rule-out criteria divided by the number of all included patients. The rule-in efficiency will be calculated as the number of patients satisfying the rule-in criteria (i.e. proceeding to advanced aortic imaging) divided by the number of all included patients. P-values will be two-sided, and a P-value lower than 0.05 will be considered as statistically significant. Analysis will be performed with the Statistical Package for the Social Sciences (SPSS) statistical package (version 17.0, SPSS Inc., Chicago, Illinois).

Trend measures: The general characteristics of the population (clinical and demographic data) will be expressed as median and interquartile range (continuous variables) and as proportions and confidence interval (95% CI; categorical variables). The confidence interval will be calculated with the Wilson method or with a generalized linear model (for likelihood ratios). The main endpoints of the study will consist of standard measures of diagnostic accuracy, i.e. sensitivity, specificity, positive and negative predictive value, positive and negative likelihood ratio. They will also be calculated as key diagnostic variables: failure rate (false negative AASs / n cases that meet the rule-out criteria) and efficacy (n cases that meet the rule-out criteria / n cases enrolled). Of each variable, the central value and the appropriate confidence interval will be defined. For statistical tests, the values of P <0.05 will be considered significant.

Sample size: The study will be sized to test the null hypothesis that the failure rate of the integrated rule-out diagnostic strategy (ADD-RS 1 / DD-) exceeds 2%. Investigators assume, based on literature data, that the punctual failure rate is 0.5%. With a type I error (alpha) of 0.05 and a type II error (beta) of 0.2, approximately 496 patients with ADD-RS1 / DDwill have to be enrolled, to reject the null hypothesis. Assuming that patients with ADD-RS1 / DD- are 30% of all subjects enrolled with the clinical suspicion of AAS, approximately 1653 patients should be analysed. Assuming a 10% rate of patients lost at follow-up, at least 1837 patients should be enrolled

Details
Condition Acute Aortic Syndrome
Clinical Study IdentifierNCT04430400
SponsorAzienda Ospedaliero-Universitaria Careggi
Last Modified on31 July 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Presence of 1 of the following symptoms, dating 14 days: neck pain, truncal (thoracic/back/abdominal) pain, syncope, organ perfusion deficit (focal neurologic deficit, limb ischemia)
AAS considered as meaningful diagnostic concern based on clinical judgement of the attending physician

Exclusion Criteria

Age <18 years
Evident alternative diagnoses to acute aortic syndromes (e.g. herpes zoster, skeletal pain)
Primary trauma
History of previous acute aortic syndrome
Patient's refusal to participate
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