Pre-Test Probability Assessment and d-Dimer Based Evaluation in Patients with Previous Acute Aortic Syndrome.

Background and Objectives. Acute aortic syndromes (AASs) are emergencies burdened by high morbidity and mortality. Guideline-recommended diagnostic workup is based on pre-test probability assessment (PPA) and d-dimer testing. However, the performance of PPA and d-dimer has never been studied in individuals with previous AAS (pAAS), which represent a challenging population. Materials and Methods. We analyzed a registry of patients with pAAS evaluated in two Emergency Departments (EDs) for suspected novel AAS (nAAS). Enrolment criteria were history of pAAS and the presence of truncal pain, syncope or perfusion deficit. All patients underwent advanced imaging. Clinical data were registered prospectively and PPA was performed by applying the aortic dissection detection (ADD) and an aorta simplified (AORTAs) score. Results. A total of 128 patients were enrolled, including 77 patients with previous Stanford type A aortic dissection and 45 patients with previous Stanford type B aortic dissection. The final diagnosis was nAAS in 40 (31%) patients. Clinical variables associated with nAAS were: aortic valve disease, thoracic aortic aneurysm, severe pain, sudden pain, ripping/tearing pain and hypotension/shock. ADD score ≥ 2 had a sensitivity of 65% and a specificity of 83% for nAAS; AORTAs score ≥ 2 had a sensitivity of 48% and a specificity of 88%. d-dimer (cutoff ≥ 500 ng/mL or age-adjusted cutoff) had a sensitivity of 97% and a specificity of 13%/14.7%, for diagnosis of nAAS. Patients that were candidates for guideline-compliant PPA/d-dimer integrated rule-out were: 5 (4.9%) with ADD ≤ 1/d-dimer and 8 (7.8%) with AORTAs ≤ 1/d-dimer < age-adjusted cutoff. None of them had a nAAS. Conclusions. Patients with pAAS evaluated in the ED for red-flag symptoms showed intermediate-to-high pre-test probability of nAAS. The ADD score had lower sensitivity and specificity than in unselected patients. d-dimer, alone and integrated with PPA, was highly sensitive for nAAS, but very unspecific. PPA/d-dimer integrated strategies are unlikely to significantly reduce the number of patients with pAAS undergoing advanced imaging.

Diagnostic Accuracy of the Aortic Dissection Detection Risk Score Plus D-Dimer for Acute Aortic Syndromes: The ADvISED Prospective Multicenter Study.

BACKGROUND: Acute aortic syndromes (AASs) are rare and severe cardiovascular emergencies with unspecific symptoms. For AASs, both misdiagnosis and overtesting are key concerns, and standardized diagnostic strategies may help physicians to balance these risks. D-dimer (DD) is highly sensitive for AAS but is inadequate as a stand-alone test. Integration of pretest probability assessment with DD testing is feasible, but the safety and efficiency of such a diagnostic strategy are currently unknown. METHODS: In a multicenter prospective observational study involving 6 hospitals in 4 countries from 2014 to 2016, consecutive outpatients were eligible if they had ≥1 of the following: chest/abdominal/back pain, syncope, perfusion deficit, and if AAS was in the differential diagnosis. The tool for pretest probability assessment was the aortic dissection detection risk score (ADD-RS, 0-3) per current guidelines. DD was considered negative (DD-) if <500 ng/mL. Final case adjudication was based on conclusive diagnostic imaging, autopsy, surgery, or 14-day follow-up. Outcomes were the failure rate and efficiency of a diagnostic strategy for ruling out AAS in patients with ADD-RS=0/DD- or ADD-RS ≤1/DD-. RESULTS: A total of 1850 patients were analyzed. Of these, 438 patients (24%) had ADD-RS=0, 1071 patients (58%) had ADD-RS=1, and 341 patients (18%) had ADD-RS >1. Two hundred forty-one patients (13%) had AAS: 125 had type A aortic dissection, 53 had type B aortic dissection, 35 had intramural aortic hematoma, 18 had aortic rupture, and 10 had penetrating aortic ulcer. A positive DD test result had an overall sensitivity of 96.7% (95% confidence interval [CI], 93.6-98.6) and a specificity of 64% (95% CI, 61.6-66.4) for the diagnosis of AAS; 8 patients with AAS had DD-. In 294 patients with ADD-RS=0/DD-, 1 case of AAS was observed. This yielded a failure rate of 0.3% (95% CI, 0.1-1.9) and an efficiency of 15.9% (95% CI, 14.3-17.6) for the ADD-RS=0/DD- strategy. In 924 patients with ADD-RS ≤1/DD-, 3 cases of AAS were observed. This yielded a failure rate of 0.3% (95% CI, 0.1-1) and an efficiency of 49.9% (95% CI, 47.7-52.2) for the ADD-RS ≤1/DD- strategy. CONCLUSIONS: Integration of ADD-RS (either ADD-RS=0 or ADD-RS ≤1) with DD may be considered to standardize diagnostic rule out of AAS. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02086136.

Rule out of acute aortic dissection with plasma matrix metalloproteinase 8 in the emergency department.

INTRODUCTION: Matrix metalloproteinases (MMPs) are involved in aortic pathophysiology. Preliminary studies have detected increased plasma levels of MMP8 and MMP9 in patients with acute aortic dissection (AAD). However, the performance of plasma MMP8 and MMP9 for the diagnosis of AAD in the emergency department is at present unknown. METHODS: The levels of MMP8 and MMP9 were measured by ELISA on plasma samples obtained from 126 consecutive patients evaluated in the emergency department for suspected AAD. All patients were subjected to urgent computed tomography (CT) scan for final diagnosis. RESULTS: In the study cohort (N = 126), AAD was diagnosed in 52 patients and ruled out in 74 patients. Median plasma MMP8 levels were 36.4 (interquartile range 24.8 to 69.3) ng/ml in patients with AAD and 13.2 (8.1 to 31.8) ng/ml in patients receiving an alternative final diagnosis (P <0.0001). Median plasma MMP9 levels were 169.2 (93.0 to 261.8) ng/ml in patients with AAD and 80.5 (41.8 to 140.6) ng/ml in patients receiving an alternative final diagnosis (P = 0.001). The area under the curve (AUC) on receiver-operating characteristic (ROC) analysis of MMP8 and MMP9 for the diagnosis of AAD was respectively 0.75 and 0.70, as compared to 0.87 of D-dimer. At the cutoff of 3.6 ng/ml, plasma MMP8 had a sensitivity of 100.0% (95% CI, 93.2% to 100.0%) and a specificity of 9.5% (95% CI, 3.9% to 18.5%) and ruled out AAD in 5.6% of patients. Combination of plasma MMP8 with D-dimer increased the AUC on ROC analysis to 0.89. Presence of MMP8 <11.0 ng/ml and D-dimer <1.0 or <2.0 µg/ml provided a negative predictive value of 100% and ruled out AAD in 13.6% and 21.4% of patients respectively. CONCLUSIONS: Low levels of plasma MMP8 can rule out AAD in a minority of patients. Combination of plasma MMP8 and D-dimer at individually suboptimal cutoffs could safely rule out AAD in a substantial proportion of patients evaluated in the emergency department.

Prospective diagnostic and prognostic study of copeptin in suspected acute aortic syndromes.

Acute aortic syndromes (AAS) are cardiovascular emergencies with unmet diagnostic needs. Copeptin is released upon stress conditions and is approved for rule-out of myocardial infarction (MI). As MI and AAS share presenting symptoms, stress mechanisms and necessity for rapid diagnosis, copeptin appears as an attractive biomarker also for AAS. We thus performed a diagnostic and observational study in Emergency Department (ED) outpatients. Inclusion criteria were chest/abdominal/back pain, syncope and/or perfusion deficit, plus AAS in differential diagnosis. Blood samples were obtained in the ED. 313 patients were analyzed and 105 (33.5%) were diagnosed with AAS. Median copeptin was 38.91 pmol/L (interquartile range, IQR, 16.33-173.4) in AAS and 7.51 pmol/L (IQR 3.58-15.08) in alternative diagnoses (P < 0.001). Copeptin (≥10 pmol/L) had a sensitivity of 80.8% (95% confidence interval, CI, 72.2-87.2) and a specificity of 63.6% (CI 56.9-69.9) for AAS. Within 6 hours, the sensitivity and specificity were 88.7% (CI 79.3-94.2) and 52.4% (CI 42.9-61.8) respectively. Combination with D-dimer did not increase the diagnostic yield. Furthermore, copeptin ≥25 pmol/L predicted mortality in patients with alternative diagnoses but not with AAS. In conclusion, copeptin increases in most patients with AAS within the first hours, but the accuracy of copeptin for diagnosis AAS is suboptimal.

White blood cell and platelet count as adjuncts to standard clinical evaluation for risk assessment in patients at low probability of acute aortic syndrome.

AIMS: Pre-test probability assessment is key in the approach to suspected acute aortic syndromes (AASs). However, most patients with AAS-compatible symptoms are classified at low probability, warranting further evaluation for decision on aortic imaging. White blood cell count, platelet count and fibrinogen explore pathophysiological pathways mobilized in AASs and are routinely assayed in the workup of AASs. However, the diagnostic performance of these variables for AASs, alone and as a bundle, is unknown. We tested the hypothesis that white blood cell count, platelet count and/or fibrinogen at presentation may be applied as additional tools to standard clinical evaluation for pre-test risk assessment in patients at low probability of AAS. METHODS AND RESULTS: This was a retrospective observational study conducted on consecutive patients managed in our Emergency Department from 2009 to 2014 for suspected AAS. White blood cell count, platelet count and fibrinogen were assayed during evaluation in the Emergency Department. The final diagnosis was obtained by computed tomography angiography. The pre-test probability of AAS was defined according to guidelines. Of 1210 patients with suspected AAS, 1006 (83.1%) were classified at low probability, and 271 (22.4%) were diagnosed with AAS. Within patients at low probability, presence of at least one alteration among white blood cell count >9*103/µl, platelet count <200*103/µl and fibrinogen <350 mg/dl was associated with a sensitivity of 95.5% (89.7-98.5%) and a specificity of 18.3% (15.6-21.2%). In patients at low probability, white blood cell count >9*103/µl and platelet count <200*103/µl were found as independent predictors of AAS beyond established clinical risk markers. Within patients at low probability, the estimated risk of AAS based on the number of alterations amongst white blood cell count >9*103/µl and platelet count <200*103/µl was 2.7% (1.2-5.7%) with zero alterations, 11.3% (8.8-14.3%) with one alteration and 31.9% (24.8-40%) with two alterations ( p<0.001). CONCLUSION: In addition to standard clinical evaluation, white blood cell count and platelet count may be used in patients at low pre-test probability to fine-tune risk assessment of AAS.

Diagnostic performance of the aortic dissection detection risk score in patients with suspected acute aortic dissection.

AIMS: The aortic dissection detection (ADD) risk score has been proposed by guidelines to standardise the approach to patients with suspected acute aortic dissection (AD). However, the ADD risk score has not been validated so far. METHODS AND RESULTS: Patients with suspected AD from two clinical centres were prospectively enrolled in a registry from 2008 to 2012. The ADD risk score was calculated retrospectively by review of medical charts, according to the number of risk categories where patients met criteria. Of 1328 patients, 291 (21.9%) were diagnosed with AD. The ADD risk score was=0 in 439 (33.1%) patients, =1 in 646 (48.6%) patients and >1 in 243 (18.3%) patients. The incidence of AD was 5.9%, 27.3% and 39.1% respectively in patient groups identified by ADD risk score=0, =1 and >1. ADD risk score>0 had a sensitivity of 91.1% (95% confidence interval (CI) 87.2-94.1%) and a specificity of 39.8% (95% CI 36.8-42.9%) for the diagnosis of AD, while ADD risk score>1 had a sensitivity of 32.7% (95% CI 27.3-38.4%) and a specificity of 85.7% (95% CI 83.5-87.8%). Among patients with ADD risk score=0, mediastinum widening on chest X-ray had a sensitivity of 16.7% (95% CI 3.6-41.4%) and a specificity of 86.3% (95% CI 81.9-90.0%). CONCLUSION: The ADD risk score stratifies patients for the risk of AD. ADD risk score>0 is highly sensitive and poorly specific for the diagnosis in AD. The presence of ADD risk score=0 per se does not accurately exclude AD. In patients with ADD risk score=0, chest X-ray provides limited diagnostic information.