Biomarkers of inflammation and thrombosis as predictors of near-term mortality in patients with peripheral arterial disease: a cohort study

Abstract

Background: Traditional atherosclerotic risk factors predict long-term cardiovascular disease events but are poor predictors of near-term events.

Objective: To determine whether elevated levels of D-dimer and biomarkers of inflammation were more closely associated with near-term than long-term mortality in patients with lower-extremity peripheral arterial disease (PAD) and whether greater increases in biomarker levels were associated with higher mortality rates during the first year after the increase than during later years.

Design: Prospective cohort study with a mean follow-up of 3.4 years.

Setting: Academic medical center.

Patients: 377 men and women with PAD.

Measurements: Mortality within 1 year after biomarker measurement, 1 to 2 years after biomarker measurement, and 2 to 3 years after biomarker measurement. Cox regression analyses were used to evaluate associations of biomarkers levels and changes in biomarkers with cardiovascular and all-cause mortality. Hazard ratios were calculated for each 1-unit increase in log1.5(biomarker level). Analyses were adjusted for age, sex, race, comorbid conditions, ankle-brachial index, and other confounders.

Results: Seventy-six patients (20%) died during follow-up. Higher levels of D-dimer, C-reactive protein, and serum amyloid A were associated with higher all-cause mortality among patients who died within 1 year after biomarker measurement (hazard ratio, 1.20 [95% CI, 1.08 to 1.33], 1.13 [CI, 1.05 to 1.21], and 1.12 [CI, 1.04 to 1.20], respectively; P < 0.001, P < 0.001, and P = 0.003) and among patients who died 1 to 2 years after biomarker measurement (hazard ratio, 1.14 [CI, 1.02 to 1.27], 1.15 [CI, 1.06 to 1.24], and 1.13 [CI, 1.04 to 1.24]; P = 0.022, P = 0.001, and P = 0.005]). However, higher levels of each biomarker were not associated with all-cause mortality for deaths occurring 2 to 3 years after biomarker measurement. Similar results were observed for cardiovascular mortality. Greater increases in each biomarker were associated with higher all-cause and cardiovascular mortality during the following year.

Limitation: The small number of deaths limited the statistical power of the analyses.

Conclusion: Among persons with PAD, circulating levels of D-dimer and inflammatory markers are higher in the 1 to 2 years before death than in periods more remote from death. Increasing levels of D-dimer and inflammatory biomarkers are independently associated with higher mortality in persons with PAD.

Conflict of interest statement

Potential Financial Conflicts of Interest: Grants received: P.M. Ridker (National Heart, Lung, and Blood Institute, National Cancer Institute, Reynolds Foundation, Doris Duke Foundation, Leducq Foundation); M.M. McDermott (National Heart, Lung, and Blood Institute). Patents received: P.M. Ridker (Brigham and Women's Hospital). Royalties: P.M. Ridker (Brigham and Women's Hospital).

Figures

Figure 1. Adjusted associations between biomarker levels and death, by interval between measurement and death

Analyses for all-cause mortality were adjusted for age, sex, race, diabetes mellitus, smoking, ankle–brachial index, number of other cardiovascular diseases, and cancer. Analyses for cardiovascular mortality were adjusted for age, sex, race, diabetes mellitus, ankle–brachial index, and number of other cardiovascular diseases. Solid squares represent the log (hazard ratio) corresponding to a 1-unit increase in the biomarker level. Error bars represent 95% CIs.

Figure 2. Adjusted associations between changes in biomarker levels from baseline to each follow-up visit and death during the year after the biomarker level change

Analyses for all-cause mortality were adjusted for age, sex, race, diabetes mellitus, smoking, ankle–brachial index, number of other cardiovascular diseases, and cancer. Analyses for cardiovascular mortality were adjusted for age, sex, race, diabetes mellitus, ankle–brachial index, and number of other cardiovascular diseases. Solid squares represent the log (hazard ratio) corresponding to a 1-unit increase in the biomarker level. Error bars represent 95% CIs. FV0 = baseline visit; FV1 = 1-year follow-up visit; FV2 = 2-year follow-up visit; FV3 = 3-year follow-up visit.

Figure 3. Rates of follow-up and death among study participants

Figure 4. Trajectories of C-reactive protein (CRP) levels over time in persons with peripheral arterial disease

The points in the survivor figure represent CRP levels in participants who survived during the following year. These individual CRP values are connected to show the trajectory of CRP levels over time in a randomly selected subset of participants who survived the 4-year follow-up. The open circles in the decedent figure represent CRP levels in participants who died during the year after CRP measurement. Individual CRP values are connected to show the trajectory of CRP levels at each visit in a randomly selected subset of participants who died during the 4-year follow-up. The boxes in each figure (survivors and decedents) represent mean CRP values for those who survived and died during the year after the measurement, respectively.

Appendix Figure 1. Trajectories of d-dimer levels over time in persons with peripheral arterial disease

The points in the survivor figure represent d-dimer levels in participants who survived during the following year. These individual d-dimer values are connected to show the trajectory of d-dimer levels over time in a randomly selected subset of participants who survived the 4-year follow-up. The open circles in the decedent figure represent d-dimer levels in participants who died during the year after d-dimer measurement. Individual d-dimer values are connected to show the trajectory of d-dimer levels at each visit in a randomly selected subset of participants who died during the 4-year follow-up. The boxes in each figure (survivors and decedents) represent mean d-dimer values for those who survived and died during the year after the measurement, respectively.

Appendix Figure 2. Trajectories of serum amyloid A levels over time in persons with peripheral arterial disease

The points in the survivor figure represent serum amyloid A levels in participants who survived during the following year. These individual serum amyloid A values are connected to show the trajectory of serum amyloid A levels over time in a randomly selected subset of participants who survived the 4-year follow-up. The open circles in the decedent figure represent serum amyloid A levels in participants who died during the year after serum amyloid A measurement. Individual serum amyloid A values are connected to show the trajectory of serum amyloid A levels at each visit in a randomly selected subset of participants who died during the 4-year follow-up. The boxes in each figure (survivors and decedents) represent mean serum amyloid A values for those who survived and died during the year after the measurement, respectively.