John Simes, Kristy P Robledo, Harvey D White, David Espinoza, Ralph A Stewart, David R Sullivan, Tanja Zeller, Wendy Hague, Paul J Nestel, Paul P Glasziou, Anthony C Keech, John Elliott, Stefan Blankenberg, Andrew M Tonkin

Background -D-dimer, a degradation product of cross-linked fibrin, is a marker for hypercoagulability and thrombotic events. Moderately elevated levels of D-dimer are associated with the risk of venous and arterial events in patients with vascular disease. We assessed the role of D-dimer levels in predicting long-term vascular outcomes, cause-specific mortality, and new cancers in the LIPID trial in the context of other risk factors. Methods -LIPID randomized patients to placebo or pravastatin 40 mg/day 5-38 months after myocardial infarction or unstable angina. D-dimer levels were measured at baseline and at 1 year. Median follow-up was 6.0 years during the trial and 16 years in total. Results -Baseline D-dimer levels for 7863 patients were grouped by quartile (≤112, 112-173, 173-273, >273 ng/mL). Higher levels were associated with older age, female sex, history of hypertension, poor renal function and elevated levels of B-natriuretic peptide, high-sensitivity C-reactive protein, and sensitive troponin I (each P<0.001). During the first 6 years, after adjustment for up to 30 additional risk factors, higher D-dimer was associated with a significantly increased risk of a major coronary event (Q4 vs Q1 HR 1.45; 95% CI 1.21-1.74), major cardiovascular (CVD) event (HR 1.45; 95% CI 1.23-1.71) and venous thromboembolism (HR 4.03 (2.31-7.03; 95% CI 2.31-7.03); each P<0.001. During the 16 years overall, higher D-dimer was an independent predictor of all-cause mortality (HR 1.59), CVD mortality (1.61), cancer mortality (1.54) and non-CVD noncancer mortality (1.57) (each P<0.001), remaining significant for deaths from each cause occurring beyond 10 years of follow-up (each P≤0.01). Higher D-dimer also independently predicted an increase in cancer incidence (HR 1.16, P=0.02).The D-dimer level increased the net reclassification index for all-cause mortality by 4.0 and venous thromboembolism by 13.6. Conclusions -D-dimer levels predict long-term risk of arterial and venous events, CVD mortality, and non-CVD noncancer mortality, independently of other risk factors. D-dimer is also a significant predictor of cancer incidence and mortality. These results support an association of D-dimer with fatal events across multiple diseases and demonstrate that this link extends beyond 10 years' follow-up.