Biomarkers of Inflammation and Thrombosis as Predictors of Near-Term Mortality in Patients with Peripheral Arterial Disease: A Cohort Study

  1. Himabindu Vidula, MD;
  2. Lu Tian, ScD;
  3. Kiang Liu, PhD;
  4. Michael H. Criqui, MD, MPH;
  5. Luigi Ferrucci, MD, PhD;
  6. William H. Pearce, MD;
  7. Philip Greenland, MD;
  8. David Green, MD, PhD;
  9. Jin Tan, MS;
  10. Daniel B. Garside, BS;
  11. Jack Guralnik, MD, PhD;
  12. Paul M Ridker, MD;
  13. Nader Rifai, PhD; and
  14. Mary M. McDermott, MD
  1. From Feinberg School of Medicine, Northwestern University, Chicago, Illinois; University of California at San Diego, San Diego, California; National Institute on Aging, Bethesda, Maryland; and Harvard Medical School and the Children's Hospital, Boston, Massachussetts.

    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.

    Article and Author Information

    • Grant Support: By grants R01-HL58099, R01-HL64739, and R01-HL076298 from the National Heart, Lung, and Blood Institute and grant RR-00048 from the National Center for Research Resources, National Institutes of Health.

    • 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).

    • Requests for Single Reprints: Mary M. McDermott, MD, 750 North Lake Shore Drive, 10th Floor, Chicago, IL 60611.

    • Current Author Addresses: Dr. Vidula: 320 Avena Circle, Naperville, IL 60565.

    • Drs. Tian, Liu, and Greenland; Mr. Tan; and Mr. Garside: 680 North Lake Shore Drive, Suite 1102, Chicago, IL 60611.

    • Dr. Criqui: University of California San Diego, Family & Preventive Medicine, 9500 Gilman Drive, La Jolla, CA 92093.

    • Dr. Ferrucci: National Institute on Aging, Clinical Research Branch, Harbor Hospital, 5th Floor, 3001 South Hanover Street, Baltimore, MD 21225.

    • Dr. Pearce: 201 East Huron, Suite 10-105, Chicago, IL 60611.

    • Dr. Green: 676 North St. Clair, Suite 850, Chicago, IL 60611.

    • Dr. Guralnik: Gateway Building, Room 3-C309, 7201 Wisconsin Avenue, Bethesda, MD 20892.

    • Dr. Ridker: Brigham and Women's Hospital, Center for Cardiovascular Disease Prevention, 900 Commonwealth Avenue, Boston, MA 02215.

    • Dr. Rifai: Children's Hospital Boston, Department of Laboratory Medicine, Farley 7, 300 Longwood Avenue, Boston, MA 02115.

    • Dr. McDermott: 750 North Lake Shore Drive, 10th Floor, Chicago, IL 60611.

    • Author Contributions: Conception and design: H. Vidula, K. Liu, M.H. Criqui, P. Greenland, D. Green, J. Guralnik, M.M. McDermott.

    • Analysis and interpretation of the data: H. Vidula, L. Tian, K. Liu, M.H. Criqui, L. Ferrucci, N. Rifai, P. Greenland, D. Green, J. Tan, J. Guralnik, P.M. Ridker.

    • Drafting of the article: H. Vidula, D. Green, M.M. McDermott.

    • Critical revision of the article for important intellectual content: H. Vidula, L. Tian, M.H. Criqui, L. Ferrucci, N. Rifai, P. Greenland, D. Green, J. Guralnik, P.M. Ridker, M.M. McDermott.

    • Final approval of the article: L. Tian, K. Liu, M.H. Criqui, L. Ferrucci, W.H. Pearce, N. Rifai, P. Greenland, D. Green, J. Guralnik, P.M. Ridker, M.M. McDermott.

    • Provision of study materials or patients: W.H. Pearce, P.M. Ridker.

    • Statistical expertise: L. Tian, K. Liu, J. Guralnik.

    • Obtaining of funding: M.H. Criqui, M.M. McDermott.

    • Administrative, technical, or logistic support: M.H. Criqui, D. Green, D.B. Garside.

    • Collection and assembly of data: D. Green, D.B. Garside, P.M. Ridker, M.M. McDermott.

    Responses to this article

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    1. Ann Intern Med January 15, 2008 vol. 148 no. 2 85-93
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