1. D-dimer level remains a highly sensitive test for acute aortic dissection beyond the first 24 hours after onset AATS Aortic Symposium 2010 ▪ New York ▪ April 29-30, 2010 Scott A. LeMaire, Ludivine Russell, Neal R. Barshes, Paul M. Allison, Dana E. Haas, Ying H. Shen, Dianna M. Milewicz, Joseph S. Coselli This study describes an unlabeled/investigational use of the Siemens Advanced D-dimer Assay, i.e. for the diagnosis of acute aortic dissection.

2. Study Objective D-dimer has been proposed as a highly sensitive biomarker to detect acute aortic dissection Elefteriades et al ▪ Cardiology 2008 Recent data from the International Registry of Acute Aortic Dissection Substudy on Biomarkers (IRAD-Bio) show that D-dimer levels obtained within the first 24 hours after symptom onset had a 96.6% sensitivity Suzuki et al ▪ Circulation 2009

3. Study Objective Some patients, particularly those with atypical symptoms, present for evaluation beyond the first 24 hours after onset of acute aortic dissection; it is unclear whether D-dimer levels would be useful in detecting dissection in these patients The purpose of this study was to determine whether D-dimer levels remain elevated more than 24 hours after the onset of acute aortic dissection

4. Methods Institutional approval was obtained for the study, and written informed consent was obtained from all patients Plasma samples were collected within 10 days after onset of symptoms from 100 patients with unrepaired acute aortic dissection Whenever possible, serial samples were obtained over a period of 2 or more days Samples were grouped according to day of collection relative to the onset of aortic dissection; an average of 25 samples were available for each day’s group, from day of onset (day 0) through post-dissection day 10

5. Clinical Features Variable Patients (n = 100) Age (yrs), mean ± SD56 ± 14 Men61 Hypertension62 Coronary artery disease4 Diabetes10 Chronic obstructive pulmonary disease11 Smoking (past or current)54 Marfan syndrome15 Cancer3

6. Dissection Characteristics Variable Patients (n = 100) DeBakey classification: Type I Type II Type III 50 12 38 Classic aortic dissection94 Intramural hematoma6 Penetrating atherosclerotic ulcer0 Drug-induced aortic dissection1 Iatrogenic aortic dissection1 Aortic rupture9

7. Methods D-dimer levels were measured in the clinical laboratory by using the Siemens Advanced D-dimer assay (latex-enhanced immunoturbidimetric assay) on an automated coagulation analyzer BCS XP (range of detection, 0.4-55 µg/mL) The approved cut-off for detecting venous thromboembolism for this assay is 1.6 µg/mL; this value was used as the diagnostic threshold A post-hoc subgroup analysis was performed to explore whether clinical factors were associated with false-negative D-dimer levels in this cohort

8. Results The median D-dimer level for all plasma samples (n = 279) was 3.56 µg/mL (interquartile range, 2.55-5.60 µg/mL) D-dimer levels exceeded the 1.6 µg/mL diagnostic threshold in 266 samples, yielding an overall sensitivity of 95.3% D-dimer levels (μg/mL) 40.0 35.0 30.0 25.0 20.0 15.0 10.0 5.0 0.0 1.6 µg/mL threshold

9. D-dimer levels remained markedly elevated throughout the 10-day post-dissection period; daily sensitivities ranged from 89 to 100% Days after onset 012 3 4 5 6 7 8 9 10 n 7 27 26 33 26 27 27 30 31 21 24 Sensitivity 100% 89% 89% 94% 100% 100% 96% 97% 97% 95%96% 1.6 µg/mL threshold D-dimer levels (μg/mL) 40.0 35.0 30.0 25.0 20.0 15.0 10.0 5.0 0.0

10. Factor False-negative Rate (D-dimer ≤ 1.6 µg/mL) P Hypertension Yes No 5/190 (3%) 8/89 (9%) 0.02 Coronary artery disease Yes No 4/20 (20%) 9/259 (3%) 0.009 DeBakey type I II III 2/84 (2%) 4/21 (19%) 7/174 (4%) 0.004 Intramural hematoma Yes No 1/17 (6%) 12/262 (5%) 0.6 False-negative results were significantly more common in samples obtained from patients without hypertension, with a history of coronary artery disease, or with DeBakey type II dissection False-negative results did not appear to be related to patient age, intramural hematoma (vs classic dissection), Marfan syndrome, smoking, or cancer

11. Conclusions Elevated D-dimer levels remain a sensitive indicator of acute aortic dissection throughout the first 10 days after onset Post-hoc analysis showed that the sensitivity of D-dimer may be reduced in certain subsets of patients, such as those with dissection involving only the ascending aorta (ie, DeBakey type II) Although D-dimer testing may be helpful in detecting acute aortic dissection in patients with delayed presentation, further studies are needed to evaluate the impact of clinical factors on the sensitivity of this assay

12. Dr. LeMaire is supported by a Thoracic Surgery Foundation for Research and Education/National Heart, Lung and Blood Institute Co-sponsored Mentored Clinical Scientist Development Award (K08 HL080085) The Thoracic Aortic Disease Tissue Bank at Baylor College of Medicine is supported in part through the NIH Specialized Center for Clinically Oriented Research in Thoracic Aortic Aneurysms and Dissections (P50 HL083794; DM Milewicz, PI) Acknowledgements