SYDNEY — A one-time high level of D-dimer predicted cardiovascular death, as well as mortality from cancer and other causes, for up to 16 years in an analysis of patients with stable CHD participating in the 1990s-era LIPID trial.[1]
The finding was independent of a range of other biomarkers and standard risk factors and suggests that D-dimer, which reflects fibrinolytic activity as a marker of conditions predisposing to thrombosis, may predict a broader range of risk outcomes over a longer time horizon than previously thought.
Knowing that elevated D-dimer is a long-term risk factor for a variety of disease outcomes, not just a short-term marker, could be of likely value in, for example, predicting how a patient might gain from any treatments under consideration, Prof John Simes (University of Sydney, Australia) explained to theheart.org | Medscape Cardiology.
That would apply to patients with a history of CHD, like those in LIPID. Whether the study’s finding that D-dimer is prognostic for cancer and non-CV, noncancer outcomes “would be worth still evaluating in more patient groups than just the one studied here,” he said.
“But I think in terms of patients with coronary disease, are these findings ready to be applied in the real world of prognosis? I think definitely,” said Simes, lead author on the study’s January 24 publication in Circulation.
LIPID had randomly assigned 9014 stable patients with a history of MI or unstable angina to receive pravastatin at 40 mg/day or placebo for a prespecified 6 years. Of those, the 7863 with baseline plasma samples available for evaluation were included in the current analysis.
Over 6 years, baseline D-dimer levels in the highest quartile, compared with the lowest quartile, predicted a 45% increased risk for CHD death, nonfatal MI, or stroke; about double the risks for CVD death and death from any cause; and a fourfold increased risk for venous thromboembolism. In the analysis adjusted for a long list of risk factors and standard biomarkers, all differences were significant at P<0.001.
With similar adjustment over an additional decade of follow-up, the highest D-dimer level quartile significantly predicted death from any cause, death from CV disease, death from cancer, and death from non-CV and noncancer causes, all at P<0.001.
Table. Hazard Ratio for Cause-Specific Mortality, Highest vs Lowest Baseline D-Dimer Quartile, in LIPIDa
| Cause-Specific Mortality | Hazard Ratio (95% CI) |
|---|---|
| Any cause | 1.59 (1.43–1.78) |
| CV disease | 1.61 (1.40–1.87) |
| Cancer | 1.54 (1.25–1.91) |
| Non-CV disease, noncancer | 1.57 (1.34–1.85) |
| aAdjusted for D-dimer quartile, pravastatin vs placebo, anticoagulant treatment, sex, stroke, diabetes, smoking, hypertension, total cholesterol, apolipoprotein B, apolipoprotein A1, HDL cholesterol, age, type of prior CHD event, timing of coronary revascularization, systolic blood pressure, atrial fibrillation, estimated glomerular filtration rate, body mass index, dyspnea class, angina grade, white blood cell count, peripheral vascular disease, triglycerides, fasting glucose, baseline aspirin, brain natriuretic peptide, high-sensitivity C-reactive protein, cystatin C, lipoprotein(a), troponin I, midregional pro-adrenomedullin, and lipoprotein-associated phospholipase A2 activity. | |
The highest baseline D-dimer quartile also predicted the risk for new cancers over 16 years (hazard ratio, 1.16; 95% CI, 1.03–1.31; P=0.02), adjusted for age, sex, smoking, C-reactive protein by high-sensitivity assay, white blood cell count, and aspirin use.
The significant reduction in rate of CV events over 6 years for patients in the trial who received the statin applied to those in all four baseline D-dimer quartiles, according to the report.
The benefits of pravastatin relative to D-dimer “were essentially the same whether you had a high or low level,” Simes said. “But that means those at higher risk tended to gain a larger absolute benefit.”
For patients with available D-dimer levels obtained at 1 year, pravastatin treatment was associated with a slight but significant reduction (P<0.001) in levels of the biomarker. But the pravastatin benefit remained significant (P<0.01) after adjustment for changes in D-dimer levels.
Noting D-dimer’s predictive power for a range of cause-specific mortality rates, Simes said it’s possible elevated levels are simply pointing to “people susceptible to dying earlier, whatever the underlying causes might be.” But some of the outcomes accounted for in the predicted risk for non-CV, noncancer mortality may have actually been unrecognized thrombotic events, such as pulmonary embolism.
“Could some of this be misclassification, where the excess may be due to unrecognized vascular events? We certainly can’t exclude that.”
LIPID was supported by a research grant from Bristol-Myers Squibb. Simes had no relevant disclosures. Potential conflicts for the other authors are in the report.
Follow Steve Stiles on Twitter: @SteveStiles2. For more from theheart.org | Medscape Cardiology, follow us on Twitter and Facebook.
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