D-Dimer in the Months Leading up to Acute Coronary Events: A Case Crossover Study
Authors: Green David , Liao Yihua , Vida Loyda , Greenland Philip , Huffman Mark D , Liu Kiang J , Lloyd-Jones Donald M , Shah Sanjiv J , Tian Lu , Tracy Russell P , Wilkins John T , Zhao Lihui , McDermott Mary M 
Published: October 2019

Abstract
Major coronary events are commonly precipitated by thrombotic occlusion of atheromatous vessels. We determined whether d-dimer, C-reactive protein (CRP), or serum amyloid A (SAA), increase in the months prior to an acute coronary events in patients with severe lower extremity peripheral artery disease (PAD).
The Biomarker Risk Assessment in Vulnerable Outpatients (BRAVO) Study enrolled patients with PAD and followed them prospectively every two months. At each visit, participants were queried about new hospitalizations, blood was obtained, electrocardiograms performed, and mortality data collected. Two controls for each patient with events were randomly selected from participants without events, matched for age, sex, race, duration in the study, and number of blood draws. D-dimer was measured using an immunoturbidometric assay (Asserachrom D-Di kit, Diagnostica Stago, Parsippany, NJ). CRP and SAA were determined using an immunotechnique on the Behring BN II analyzer (Dade Behring, Wilmington, DE). Changes in levels of these biomarkers during the months leading up to the primary outcome (acute MI, new MI detected by ECG, hospitalization for unstable angina, cardiac death) were the independent variables of interest.
A total of 595 participants with PAD were followed for a mean of 1.56 years; 50 (8.4%) experienced 75 acute coronary events. Sixteen of these cases had five complete visits immediately prior to the event, allowing a comparison of D-dimer levels over time within the same cohort of study participants. Their median/interquartile D-dimer (mg/L, log-transformed) just prior to the event was 1.05 (0.62-1.62); the level was significantly lower at each of the other 4 visits (0.69, 0.71, 0.83, 0.86; all P <0.032 based on paired t-tests). We also compared cases with controls; in 19 cases (36 pairs with controls), D-dimer measurements at the 4 visits leading up to an acute event were significantly higher in the cases than in the controls (Table 1).
CRP (mg/L) was increased just prior to events only in comparison with visits at 4 and 8 months (n=16; 3.34 vs 2.29, P=0.03; 3.34 vs 1.94, P=0.02), and was not significantly higher in cases than controls. SAA (mg/L) just prior to an event exceeded only one other value (at 8 months; 0.55 vs 0.37, P=0.02), and was higher in cases than controls at only 1 visit.
We conclude that levels of D-dimer are significantly higher within 2 months of an acute coronary event compared to values in the same participants in the months before the event. In addition, D-dimer levels are higher in patients than controls during the 8 month period before an acute coronary event. Levels of CRP and SAA are infrequently increased in patients prior to events and in comparison to those without events.
Table 1. Median D-dimer (mg/L) during the 8 months leading up to an ischemic heart disease event. Cases vs Controls No. of pairs/cases Median/Interquartile for case Median/Interquartile for control P-value from GEE* Within 2 months 36/19 1.1 (0.62 to 1.67) 0.53 (0.3 to 0.84) 0.01 4 months 36/19 0.95 (0.52 to 1.55) 0.45 (0.28 to 0.9) 0.03 6 months 36/19 0.83 (0.52 to 1.76) 0.5 (0.27 to 0.91) 0.02 8 months 36/19 0.86 (0.48 to 1.45) 0.48 (0.3 to 0.9) 0.01
*P-value based on the General Estimating Equation (GEE) model using LOG transformed values and assuming correlated error structure

Disclosures
Huffman: AstraZeneca: Research Funding; Boehringer Ingelheim: Research Funding.