It’s Time to Use an Age-based Approach to D-dimer

PRACTICE CHANGER

Use an age-adjusted d-dimer cutoff (patient age in years × 10 μg/L) for patients older than 50 when evaluating for venous thromboembolism (VTE); it reduces false-positives without substantially increasing false-negatives.¹

STRENGTH OF RECOMMENDATION

A: Based on consistent and good-quality patient-centered evidence from a meta-analysis of cohort studies.¹

ILLUSTRATIVE CASE

A 78-year-old woman with no significant medical history or recent immobility comes to your clinic complaining of left lower extremity pain and swelling. Her d-dimer is 650 μg/L. What is your next step?

Although d-dimer is recognized as a reasonable screening tool for VTE, the specificity of d-dimer testing using a conventional cutoff value of 500 μg/L is particularly poor in patients older than 50. In low-risk patients older than 80, the specificity is 14.7%.^2-5 As a result, conventional d-dimer testing is not very helpful for ruling out VTE in older patients.^2-5

Improved testing is needed for a population at heightened risk

In the United States, there are more than 600,000 cases of deep vein thrombosis (DVT) and pulmonary embolism (PE) each year.² The incidence of PE increases from 1:1,000 in younger patients to 8:1,000 in older patients,⁴ and the mortality rate can reach 30%.⁶ The gold standards of venography and pulmonary angiography have been replaced by less burdensome tests, primarily lower extremity duplex ultrasound and CT pulmonary angiogram. However, even these tests are expensive and often present logistical challenges in elderly patients. For these reasons, it is helpful to have a simple, less-expensive tool to rule out VTE in older patients who have signs or symptoms.

Continued on next page >>

STUDY SUMMARY

Using age-adjusted d-dimer cutoffs significantly reduced false-positives

Schouten et al¹ performed a systematic review and meta-analysis of studies of older patients with suspected VTE who had d-dimer testing using both conventional and age-adjusted cutoff values. The authors searched Medline and Embase for studies that were performed in outpatient, inpatient, or emergency department settings. They excluded studies of high-risk patients, specifically perioperative patients and those who’d had VTE, cancer, or a coagulation disorder.

Five high-quality studies of 13 cohorts were included in this analysis (N = 12,497; 6,969 patients older than 50). Each of these studies was a retrospective analysis of patients with a low clinical probability of VTE, as determined by Geneva or Wells scoring. The authors calculated the VTE prevalence and d-dimer sensitivity and specificity for patients ages ≤ 50, 51 to 60, 61 to 70, 71 to 80, and > 80.

The specificity of the conventional d-dimer cutoff value for VTE decreased with age from 57.6% in those ages 51 to 60 to 14.7% in those older than 80. When age-adjusted cutoffs were used (age in years × 10 μg/L), specificities improved in all age categories, particularly for older patients. For example, using age-adjusted cutoff values improved specificity to 62.3% in patients ages 51 to 60 and to 35.2% in those older than 80 (see table). Using a hypothetical model, Schouten et al¹ calculated that applying age-adjusted cutoff values would exclude VTE in 303/1,000 patients older than 80, compared with 124/1,000 when using the conventional cutoff.

The benefit of using an age-adjusted cutoff is the ability to exclude VTE in more patients (1 out of 3 in those older than 80) while not significantly increasing the number of missed VTE. In fact, the number of missed cases in the older population using the age-adjusted cutoff (approximately 1 to 4 per 1,000 patients) is comparable to the false-negative rate in those ages 50 and younger (3 per 1,000). The advantages are most notable with the use of enzyme linked fluorescent assays because these assays have a higher sensitivity and a trend toward lower specificity compared with other assays.

Continued on next page >>

WHAT’S NEW?

We can now use d-dimer in older patients

Up until now, it was acknowledged that the simple and less expensive d-dimer test was less useful for older patients. In fact, in their 2007 clinical practice guideline on the diagnosis of VTE in primary care, the American Academy of Family Physicians and the American College of Physicians commented on the poor performance of the test in older patients.² A more recent guideline—released by the Institute for Clinical Systems Improvement in January 2013—provided no specific guidance for patients older than 50.⁷ The meta-analysis reported on here, however, provides that guidance: Using an age-adjusted d-dimer cutoff improves the diagnostic accuracy of d-dimer screening in older adults.

CAVEATS

Results are not generalizable to patients at higher risk

These findings are not generalizable to all patients, particularly those at higher clinical risk who would undergo imaging regardless of d-dimer results. Not all patients included in this meta-analysis whose d-dimer was negative received imaging to confirm that they did not have VTE. As a result, the diagnostic accuracy of the age-adjusted cutoff could have been overestimated, although this is likely not clinically important because these cases would have remained symptomatic within the 45-day to 3-month follow-up period.

CHALLENGES TO IMPLEMENTATION

You, not the lab, will need to do the calculation

One of the more valuable aspects of this study is its identification of a simple calculation that can directly improve patient care. Clinicians can easily apply an age-adjusted d-dimer cutoff as they interpret lab results by multiplying the patient’s age in years × 10 μg/L. While this does not require institutional changes by the lab, hospital, or clinic, it would be helpful if the age-adjusted d-dimer calculation was provided with the lab results.

REFERENCES

1. Schouten HJ, Geersing GJ, Koek HL, et al. Diagnostic accuracy of conventional or age adjusted D-dimer cut-off values in older patients with suspected venous thromboembolism: systematic review and meta-analysis. BMJ. 2013;346: f2492.

2. Qaseem A, Snow V, Barry P, et al; Joint American Academy of Family Physicians/American College of Physicians Panel on Deep Venous Thrombosis/Pulmonary Embolism. Current diagnosis of venous thromboembolism in primary care: a clinical practice guideline from the American Academy of Family Physicians and the American College of Physicians. Ann Fam Med. 2007;5:57-62.

3. Vossen JA, Albrektson J, Sensarma A, et al. Clinical usefulness of adjusted D-dimer cutoff values to exclude pulmonary embolism in a community hospital emergency department patient population. Acta Radiol. 2012;53:
765-768.

4. van Es J, Mos I, Douma R, et al. The combination of four different clinical decision rules and an age-adjusted D-dimer cut-off increases the number of patients in whom acute pulmonary embolism can safely be excluded. Thromb Haemost. 2012;107:167-171.

5. Deep vein thrombosis (DVT). DynaMed Web site. http://bit.ly/1gPkLoE. Accessed March 3, 2014.

6. Horlander KT, Mannino DM, Leeper KV. Pulmonary embolism mortality in the United States, 1979–1998: an analysis using multiple-cause mortality data. Arch Intern Med. 2003;163:1711-1717.

7. Dupras D, Bluhm J, Felty C, et al. Venous thromboembolism diagnosis and treatment. Institute for Clinical Systems Improvement Web site. Available at: https://www.icsi.org/_asset/sw0pgp/VTE.pdf. Accessed March 3, 2014.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

Copyright © 2014. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2014;63(3):155-156, 158.

PRACTICE CHANGER

Use an age-adjusted d-dimer cutoff (patient age in years × 10 μg/L) for patients older than 50 when evaluating for venous thromboembolism (VTE); it reduces false-positives without substantially increasing false-negatives.¹

STRENGTH OF RECOMMENDATION

A: Based on consistent and good-quality patient-centered evidence from a meta-analysis of cohort studies.¹

ILLUSTRATIVE CASE

A 78-year-old woman with no significant medical history or recent immobility comes to your clinic complaining of left lower extremity pain and swelling. Her d-dimer is 650 μg/L. What is your next step?

Although d-dimer is recognized as a reasonable screening tool for VTE, the specificity of d-dimer testing using a conventional cutoff value of 500 μg/L is particularly poor in patients older than 50. In low-risk patients older than 80, the specificity is 14.7%.^2-5 As a result, conventional d-dimer testing is not very helpful for ruling out VTE in older patients.^2-5

Improved testing is needed for a population at heightened risk

In the United States, there are more than 600,000 cases of deep vein thrombosis (DVT) and pulmonary embolism (PE) each year.² The incidence of PE increases from 1:1,000 in younger patients to 8:1,000 in older patients,⁴ and the mortality rate can reach 30%.⁶ The gold standards of venography and pulmonary angiography have been replaced by less burdensome tests, primarily lower extremity duplex ultrasound and CT pulmonary angiogram. However, even these tests are expensive and often present logistical challenges in elderly patients. For these reasons, it is helpful to have a simple, less-expensive tool to rule out VTE in older patients who have signs or symptoms.

Continued on next page >>

STUDY SUMMARY

Using age-adjusted d-dimer cutoffs significantly reduced false-positives

Schouten et al¹ performed a systematic review and meta-analysis of studies of older patients with suspected VTE who had d-dimer testing using both conventional and age-adjusted cutoff values. The authors searched Medline and Embase for studies that were performed in outpatient, inpatient, or emergency department settings. They excluded studies of high-risk patients, specifically perioperative patients and those who’d had VTE, cancer, or a coagulation disorder.

Five high-quality studies of 13 cohorts were included in this analysis (N = 12,497; 6,969 patients older than 50). Each of these studies was a retrospective analysis of patients with a low clinical probability of VTE, as determined by Geneva or Wells scoring. The authors calculated the VTE prevalence and d-dimer sensitivity and specificity for patients ages ≤ 50, 51 to 60, 61 to 70, 71 to 80, and > 80.

The specificity of the conventional d-dimer cutoff value for VTE decreased with age from 57.6% in those ages 51 to 60 to 14.7% in those older than 80. When age-adjusted cutoffs were used (age in years × 10 μg/L), specificities improved in all age categories, particularly for older patients. For example, using age-adjusted cutoff values improved specificity to 62.3% in patients ages 51 to 60 and to 35.2% in those older than 80 (see table). Using a hypothetical model, Schouten et al¹ calculated that applying age-adjusted cutoff values would exclude VTE in 303/1,000 patients older than 80, compared with 124/1,000 when using the conventional cutoff.

The benefit of using an age-adjusted cutoff is the ability to exclude VTE in more patients (1 out of 3 in those older than 80) while not significantly increasing the number of missed VTE. In fact, the number of missed cases in the older population using the age-adjusted cutoff (approximately 1 to 4 per 1,000 patients) is comparable to the false-negative rate in those ages 50 and younger (3 per 1,000). The advantages are most notable with the use of enzyme linked fluorescent assays because these assays have a higher sensitivity and a trend toward lower specificity compared with other assays.

Continued on next page >>

WHAT’S NEW?

We can now use d-dimer in older patients

Up until now, it was acknowledged that the simple and less expensive d-dimer test was less useful for older patients. In fact, in their 2007 clinical practice guideline on the diagnosis of VTE in primary care, the American Academy of Family Physicians and the American College of Physicians commented on the poor performance of the test in older patients.² A more recent guideline—released by the Institute for Clinical Systems Improvement in January 2013—provided no specific guidance for patients older than 50.⁷ The meta-analysis reported on here, however, provides that guidance: Using an age-adjusted d-dimer cutoff improves the diagnostic accuracy of d-dimer screening in older adults.

CAVEATS

Results are not generalizable to patients at higher risk

These findings are not generalizable to all patients, particularly those at higher clinical risk who would undergo imaging regardless of d-dimer results. Not all patients included in this meta-analysis whose d-dimer was negative received imaging to confirm that they did not have VTE. As a result, the diagnostic accuracy of the age-adjusted cutoff could have been overestimated, although this is likely not clinically important because these cases would have remained symptomatic within the 45-day to 3-month follow-up period.

CHALLENGES TO IMPLEMENTATION

You, not the lab, will need to do the calculation

One of the more valuable aspects of this study is its identification of a simple calculation that can directly improve patient care. Clinicians can easily apply an age-adjusted d-dimer cutoff as they interpret lab results by multiplying the patient’s age in years × 10 μg/L. While this does not require institutional changes by the lab, hospital, or clinic, it would be helpful if the age-adjusted d-dimer calculation was provided with the lab results.

REFERENCES

1. Schouten HJ, Geersing GJ, Koek HL, et al. Diagnostic accuracy of conventional or age adjusted D-dimer cut-off values in older patients with suspected venous thromboembolism: systematic review and meta-analysis. BMJ. 2013;346: f2492.

2. Qaseem A, Snow V, Barry P, et al; Joint American Academy of Family Physicians/American College of Physicians Panel on Deep Venous Thrombosis/Pulmonary Embolism. Current diagnosis of venous thromboembolism in primary care: a clinical practice guideline from the American Academy of Family Physicians and the American College of Physicians. Ann Fam Med. 2007;5:57-62.

3. Vossen JA, Albrektson J, Sensarma A, et al. Clinical usefulness of adjusted D-dimer cutoff values to exclude pulmonary embolism in a community hospital emergency department patient population. Acta Radiol. 2012;53:
765-768.

4. van Es J, Mos I, Douma R, et al. The combination of four different clinical decision rules and an age-adjusted D-dimer cut-off increases the number of patients in whom acute pulmonary embolism can safely be excluded. Thromb Haemost. 2012;107:167-171.

5. Deep vein thrombosis (DVT). DynaMed Web site. http://bit.ly/1gPkLoE. Accessed March 3, 2014.

6. Horlander KT, Mannino DM, Leeper KV. Pulmonary embolism mortality in the United States, 1979–1998: an analysis using multiple-cause mortality data. Arch Intern Med. 2003;163:1711-1717.

7. Dupras D, Bluhm J, Felty C, et al. Venous thromboembolism diagnosis and treatment. Institute for Clinical Systems Improvement Web site. Available at: https://www.icsi.org/_asset/sw0pgp/VTE.pdf. Accessed March 3, 2014.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

Copyright © 2014. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2014;63(3):155-156, 158.

PRACTICE CHANGER

Use an age-adjusted d-dimer cutoff (patient age in years × 10 μg/L) for patients older than 50 when evaluating for venous thromboembolism (VTE); it reduces false-positives without substantially increasing false-negatives.¹

STRENGTH OF RECOMMENDATION

A: Based on consistent and good-quality patient-centered evidence from a meta-analysis of cohort studies.¹

ILLUSTRATIVE CASE

A 78-year-old woman with no significant medical history or recent immobility comes to your clinic complaining of left lower extremity pain and swelling. Her d-dimer is 650 μg/L. What is your next step?

Although d-dimer is recognized as a reasonable screening tool for VTE, the specificity of d-dimer testing using a conventional cutoff value of 500 μg/L is particularly poor in patients older than 50. In low-risk patients older than 80, the specificity is 14.7%.^2-5 As a result, conventional d-dimer testing is not very helpful for ruling out VTE in older patients.^2-5

Improved testing is needed for a population at heightened risk

In the United States, there are more than 600,000 cases of deep vein thrombosis (DVT) and pulmonary embolism (PE) each year.² The incidence of PE increases from 1:1,000 in younger patients to 8:1,000 in older patients,⁴ and the mortality rate can reach 30%.⁶ The gold standards of venography and pulmonary angiography have been replaced by less burdensome tests, primarily lower extremity duplex ultrasound and CT pulmonary angiogram. However, even these tests are expensive and often present logistical challenges in elderly patients. For these reasons, it is helpful to have a simple, less-expensive tool to rule out VTE in older patients who have signs or symptoms.

Continued on next page >>

STUDY SUMMARY

Using age-adjusted d-dimer cutoffs significantly reduced false-positives

Schouten et al¹ performed a systematic review and meta-analysis of studies of older patients with suspected VTE who had d-dimer testing using both conventional and age-adjusted cutoff values. The authors searched Medline and Embase for studies that were performed in outpatient, inpatient, or emergency department settings. They excluded studies of high-risk patients, specifically perioperative patients and those who’d had VTE, cancer, or a coagulation disorder.

Five high-quality studies of 13 cohorts were included in this analysis (N = 12,497; 6,969 patients older than 50). Each of these studies was a retrospective analysis of patients with a low clinical probability of VTE, as determined by Geneva or Wells scoring. The authors calculated the VTE prevalence and d-dimer sensitivity and specificity for patients ages ≤ 50, 51 to 60, 61 to 70, 71 to 80, and > 80.

The specificity of the conventional d-dimer cutoff value for VTE decreased with age from 57.6% in those ages 51 to 60 to 14.7% in those older than 80. When age-adjusted cutoffs were used (age in years × 10 μg/L), specificities improved in all age categories, particularly for older patients. For example, using age-adjusted cutoff values improved specificity to 62.3% in patients ages 51 to 60 and to 35.2% in those older than 80 (see table). Using a hypothetical model, Schouten et al¹ calculated that applying age-adjusted cutoff values would exclude VTE in 303/1,000 patients older than 80, compared with 124/1,000 when using the conventional cutoff.

The benefit of using an age-adjusted cutoff is the ability to exclude VTE in more patients (1 out of 3 in those older than 80) while not significantly increasing the number of missed VTE. In fact, the number of missed cases in the older population using the age-adjusted cutoff (approximately 1 to 4 per 1,000 patients) is comparable to the false-negative rate in those ages 50 and younger (3 per 1,000). The advantages are most notable with the use of enzyme linked fluorescent assays because these assays have a higher sensitivity and a trend toward lower specificity compared with other assays.

Continued on next page >>

WHAT’S NEW?

We can now use d-dimer in older patients

Up until now, it was acknowledged that the simple and less expensive d-dimer test was less useful for older patients. In fact, in their 2007 clinical practice guideline on the diagnosis of VTE in primary care, the American Academy of Family Physicians and the American College of Physicians commented on the poor performance of the test in older patients.² A more recent guideline—released by the Institute for Clinical Systems Improvement in January 2013—provided no specific guidance for patients older than 50.⁷ The meta-analysis reported on here, however, provides that guidance: Using an age-adjusted d-dimer cutoff improves the diagnostic accuracy of d-dimer screening in older adults.

CAVEATS

Results are not generalizable to patients at higher risk

These findings are not generalizable to all patients, particularly those at higher clinical risk who would undergo imaging regardless of d-dimer results. Not all patients included in this meta-analysis whose d-dimer was negative received imaging to confirm that they did not have VTE. As a result, the diagnostic accuracy of the age-adjusted cutoff could have been overestimated, although this is likely not clinically important because these cases would have remained symptomatic within the 45-day to 3-month follow-up period.

CHALLENGES TO IMPLEMENTATION

You, not the lab, will need to do the calculation

One of the more valuable aspects of this study is its identification of a simple calculation that can directly improve patient care. Clinicians can easily apply an age-adjusted d-dimer cutoff as they interpret lab results by multiplying the patient’s age in years × 10 μg/L. While this does not require institutional changes by the lab, hospital, or clinic, it would be helpful if the age-adjusted d-dimer calculation was provided with the lab results.

REFERENCES

1. Schouten HJ, Geersing GJ, Koek HL, et al. Diagnostic accuracy of conventional or age adjusted D-dimer cut-off values in older patients with suspected venous thromboembolism: systematic review and meta-analysis. BMJ. 2013;346: f2492.

2. Qaseem A, Snow V, Barry P, et al; Joint American Academy of Family Physicians/American College of Physicians Panel on Deep Venous Thrombosis/Pulmonary Embolism. Current diagnosis of venous thromboembolism in primary care: a clinical practice guideline from the American Academy of Family Physicians and the American College of Physicians. Ann Fam Med. 2007;5:57-62.

3. Vossen JA, Albrektson J, Sensarma A, et al. Clinical usefulness of adjusted D-dimer cutoff values to exclude pulmonary embolism in a community hospital emergency department patient population. Acta Radiol. 2012;53:
765-768.

4. van Es J, Mos I, Douma R, et al. The combination of four different clinical decision rules and an age-adjusted D-dimer cut-off increases the number of patients in whom acute pulmonary embolism can safely be excluded. Thromb Haemost. 2012;107:167-171.

5. Deep vein thrombosis (DVT). DynaMed Web site. http://bit.ly/1gPkLoE. Accessed March 3, 2014.

6. Horlander KT, Mannino DM, Leeper KV. Pulmonary embolism mortality in the United States, 1979–1998: an analysis using multiple-cause mortality data. Arch Intern Med. 2003;163:1711-1717.

7. Dupras D, Bluhm J, Felty C, et al. Venous thromboembolism diagnosis and treatment. Institute for Clinical Systems Improvement Web site. Available at: https://www.icsi.org/_asset/sw0pgp/VTE.pdf. Accessed March 3, 2014.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

Copyright © 2014. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2014;63(3):155-156, 158.