Kate Kirley, MD

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older patients,⁴ and the mortality rate can reach 30%.⁶ The gold standards of venography and pulmonary angiography have been replaced by less burdensome tests, primarily lower extremity duplex ultrasound and CT pulmonary angiogram.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.

Illustrative case

A 78-year-old woman with no significant past medical history or recent immobility comes into your clinic complaining of left lower extremity pain and swelling. Her D-dimer is 650 mcg/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 mcg/L is particularly poor in patients over 50 years. In low-risk patients over 80 years old, the specificity is 14.7% (95% confidence interval, 11.3%-18.6%).^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 1:1000 in younger patients to 8:1000 in older patients⁴ 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 computed tomography 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.

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 published before June 21, 2012 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; 6969 patients >50 years). 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 years.

The specificity of using the conventional D-dimer cutoff value for VTE (500 mcg/L) 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 mcg/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 (TABLE). Using a hypothetical model, Schouten et al¹ calculated that applying age-adjusted cutoff values would exclude VTE in 303/1000 patients >80 years, compared with 124/1000 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 age 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 1000 patients) is comparable to the false negative rate in those age, ≤50 (3 per 1000). The advantages of an age-adjusted cutoff 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.

WHAT'S NEW?: We can now make use of the D-dimer in older patients

Up until now, it was acknowledged that the simple and less expensive D-dimer test was less useful for our 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 over age 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 using an 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 it identifies a simple calculation that can directly improve patient care. Physicians can easily apply an age-adjusted D-dimer cutoff as they interpret lab results by multiplying the patient’s age in years × 10 mcg/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.

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.

Illustrative case

A 78-year-old woman with no significant past medical history or recent immobility comes into your clinic complaining of left lower extremity pain and swelling. Her D-dimer is 650 mcg/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 mcg/L is particularly poor in patients over 50 years. In low-risk patients over 80 years old, the specificity is 14.7% (95% confidence interval, 11.3%-18.6%).^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 1:1000 in younger patients to 8:1000 in older patients⁴ 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 computed tomography 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.

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 published before June 21, 2012 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; 6969 patients >50 years). 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 years.

The specificity of using the conventional D-dimer cutoff value for VTE (500 mcg/L) 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 mcg/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 (TABLE). Using a hypothetical model, Schouten et al¹ calculated that applying age-adjusted cutoff values would exclude VTE in 303/1000 patients >80 years, compared with 124/1000 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 age 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 1000 patients) is comparable to the false negative rate in those age, ≤50 (3 per 1000). The advantages of an age-adjusted cutoff 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.

WHAT'S NEW?: We can now make use of the D-dimer in older patients

Up until now, it was acknowledged that the simple and less expensive D-dimer test was less useful for our 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 over age 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 using an 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 it identifies a simple calculation that can directly improve patient care. Physicians can easily apply an age-adjusted D-dimer cutoff as they interpret lab results by multiplying the patient’s age in years × 10 mcg/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.

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.

Illustrative case

A 78-year-old woman with no significant past medical history or recent immobility comes into your clinic complaining of left lower extremity pain and swelling. Her D-dimer is 650 mcg/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 mcg/L is particularly poor in patients over 50 years. In low-risk patients over 80 years old, the specificity is 14.7% (95% confidence interval, 11.3%-18.6%).^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 1:1000 in younger patients to 8:1000 in older patients⁴ 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 computed tomography 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.

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 published before June 21, 2012 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; 6969 patients >50 years). 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 years.

The specificity of using the conventional D-dimer cutoff value for VTE (500 mcg/L) 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 mcg/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 (TABLE). Using a hypothetical model, Schouten et al¹ calculated that applying age-adjusted cutoff values would exclude VTE in 303/1000 patients >80 years, compared with 124/1000 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 age 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 1000 patients) is comparable to the false negative rate in those age, ≤50 (3 per 1000). The advantages of an age-adjusted cutoff 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.

WHAT'S NEW?: We can now make use of the D-dimer in older patients

Up until now, it was acknowledged that the simple and less expensive D-dimer test was less useful for our 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 over age 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 using an 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 it identifies a simple calculation that can directly improve patient care. Physicians can easily apply an age-adjusted D-dimer cutoff as they interpret lab results by multiplying the patient’s age in years × 10 mcg/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.

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.

PRACTICE CHANGER
Recommend that patients taking antibiotics also take probiotics, which have been found to be effective both for the prevention and treatment of antibiotic-associated diarrhea (AAD).¹

STRENGTH OF

RECOMMENDATION
A: Based on a systematic review and meta-analysis of randomized controlled trials (RCTs).

ILLUSTRATIVE CASE
When you prescribe an antibiotic for a 45-year-old patient with Helicobacter pylori, he worries that the medication will cause diarrhea. Should you recommend that he take probiotics?

More than a third of patients taking antibiotics develop AAD,² and in 17% of cases, AAD is fatal.^3,4 Although the diarrhea may be the result of increased gastrointestinal (GI) motility in some cases, a disruption of the GI flora that normally acts as a barrier to infection and aids in the digestion of carbohydrates is a far more common cause.

Morbidity and mortality are high
AAD is associated with several pathogens, including Clostridium difficile, Clostridium perfringens, Klebsiella oxytoca, and Staphylococcus aureus,² and varies widely in severity. Pseudomembranous colitis secondary to C difficile is the main cause of AAD-related mortality, which more than doubled from 2002 to 2009.^3,4 C difficile infections cost the US health care system up to $1.3 billion annually.⁵ With such high rates of morbidity and mortality and high health care costs associated with AAD, even a small reduction in the number of cases would have a big impact.

Probiotics replenish the natural GI flora with nonpathogenic organisms. A 2006 meta-analysis of 31 RCTs assessing the efficacy of probiotics for both the prevention of AAD and treatment of C difficile found a pooled relative risk (RR) of 0.43 for AAD in the patients taking probiotics.⁶ However, many of the studies included in that meta-analysis were small. As a result, in 2010, the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA) recommended against the use of probiotics for the prevention of primary C difficile infection, citing a lack of high-quality evidence.⁷

Nonetheless, that same year, 98% of gastroenterologists surveyed expressed a belief that probiotics had a role in the treatment of GI illness.⁸ And in 2011, the Third Yale Working Group on Probiotic Use published recommendations for probiotic use based on expert opinion.⁹ The meta-analysis detailed in this PURL, which included more than 30 trials published since the 2006 meta-analysis, addressed the efficacy of probiotics for prevention and treatment of AAD.

STUDY SUMMARY
Probiotics significantly reduce AAD
Hempel et al reviewed 82 studies and pooled data from 63 RCTs (N = 11,811) to identify the RR of AAD among patients who received probiotics during antibiotic treatment, compared with those who received no probiotics or were given a placebo.¹ The studies encompassed a variety of antibiotics, taken alone or in combination, and several probiotics, including Lactobacillus, Bifidobacterium, Saccharomyces, and some combinations.

The outcome: The pooled RR for AAD in the probiotics groups was 0.58, with a number needed to treat of 13. Although the authors reported that the overall quality of the included trials was poor, a sensitivity analysis of the higher-quality studies yielded similar results.

Subgroup analyses by type of probiotic and duration of antibiotic treatment were also consistent with the overall pooled RR. In subgroup analysis by age, a similar decrease in AAD was found among the youngest patients (ages 0 to 17) and those between the ages of 17 and 65. Among patients older than 65—for whom there were just three studies—a nonsignificant decrease in risk was found. Twenty-three of the studies assessed adverse outcomes, of which none were reported.

WHAT'S NEW
A reason to pair antibiotics and probiotics
This meta-analysis reached a similar conclusion to the 2006 meta-analysis: Probiotics appear to be effective in preventing and treating AAD in children and adults receiving a wide variety of antibiotics for a number of conditions. The results were also consistent with those of a new meta-analysis that looked specifically at one pathogen—and found a reduction of 66% in C difficile–associated diarrhea in patients taking probiotics with their antibiotics.¹⁰

CAVEATS
Limited data on the safety

of probiotics exist
There was some heterogeneity among the studies in the meta-analysis by Hempel et al,¹ and some of the studies were of poor quality. Because of this, the authors used subgroup and sensitivity analysis, which supported their initial conclusion.

Probiotics have generally been considered safe; however, there have been rare reports of sepsis and fungemia associated with probiotic use, especially in immunosuppressed patients.¹ Fifty-nine of the included studies did not assess adverse events, which limited the ability of this meta-analysis to assess safety.¹ Patients taking probiotics should be monitored for adverse effects.

CHALLENGES TO IMPLEMENTATION
Lack of guidance on dosing and duration
Since probiotics are considered food supplements, health insurance will not cover the cost (which will likely be more than $20 per month). No single probiotic strain has high-quality evidence; however, most of the RCTs included in the meta-analysis used combinations of Lactobacillus species, which are usually found in OTC antidiarrheal probiotic supplements. No standard dose exists, but dose ranges in RCTs are 107 to 1010 colony-forming units per capsule (taken one to three times daily);¹ however, product labels have variable accuracy.¹¹ The duration of treatment ranges from one to three weeks—or as long as the patient continues to take antibiotics. .

REFERENCES
1. Hempel S, Newberry S, Maher A, et al. Probiotics for the prevention and treatment of antibiotic-associated diarrhea. JAMA. 2012; 307:1959-1969.

2. McFarland LV. Antibiotic-associated diarrhea: epidemiology, trends and treatment. Future Microbiol. 2008;3:563-578.

3. Pepin J, Valiquette L, Cossette B. Mortality attributable to nosocomial Clostridium difficile–associated disease during an epidemic caused by a hypervirulent strain in Quebec. CMAJ. 2005;173:1037-1042.

4. Perry A, Dellon E, Lund J, et al. Burden of gastrointestinal disease in the United States: 2012 Update. Gastroenterology. 2012;143: 1179-1187.

5. Dubberke E, Wertheimer A. A review of current literature on the economic burden of Clostridium difficile infection. Infect Control Hosp Epidemiol. 2009;30:57-66.

6. McFarland L. Meta-analysis of probiotics for the prevention of antibiotic associated diarrhea and the treatment of Clostridium difficile disease. Am J Gastroenterol. 2006;101:

812-822.

7. Cohen S, Gerding D, Johnson S, et al. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America and the Infectious Diseases Society of America. Infect Control Hosp Epidemiol. 2010;31: 431-455.

8. Williams M, Ha C, Ciorba M. Probiotics as therapy in gastroenterology. J Clin Gastroenterol. 2010;44:631-636.

9. Floch M, Walker A, Madsne K, et al. Recommendations for probiotic use—2011 update. J Clin Gastroenterol. 2011;45(suppl):S168-S171.

10. Johnston BC, Ma SS, Goldenberg JZ, et al. Probiotics for the prevention of Clostridium difficile–associated diarrhea: a systematic review and meta-analysis. Ann Intern Med. 2012;157:878-888.

11. Hamilton-Miller J, Shah S. Deficiencies in microbiological quality and labeling of probiotic supplements. Int J Food Microbiol. 2002; 72:175-176.

Acknowledgement
The PURLs Surveillance System was developed with support from 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 © 2012. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2012;61:673-674.

PRACTICE CHANGER
Recommend that patients taking antibiotics also take probiotics, which have been found to be effective both for the prevention and treatment of antibiotic-associated diarrhea (AAD).¹

STRENGTH OF

RECOMMENDATION
A: Based on a systematic review and meta-analysis of randomized controlled trials (RCTs).

ILLUSTRATIVE CASE
When you prescribe an antibiotic for a 45-year-old patient with Helicobacter pylori, he worries that the medication will cause diarrhea. Should you recommend that he take probiotics?

More than a third of patients taking antibiotics develop AAD,² and in 17% of cases, AAD is fatal.^3,4 Although the diarrhea may be the result of increased gastrointestinal (GI) motility in some cases, a disruption of the GI flora that normally acts as a barrier to infection and aids in the digestion of carbohydrates is a far more common cause.

Morbidity and mortality are high
AAD is associated with several pathogens, including Clostridium difficile, Clostridium perfringens, Klebsiella oxytoca, and Staphylococcus aureus,² and varies widely in severity. Pseudomembranous colitis secondary to C difficile is the main cause of AAD-related mortality, which more than doubled from 2002 to 2009.^3,4 C difficile infections cost the US health care system up to $1.3 billion annually.⁵ With such high rates of morbidity and mortality and high health care costs associated with AAD, even a small reduction in the number of cases would have a big impact.

Probiotics replenish the natural GI flora with nonpathogenic organisms. A 2006 meta-analysis of 31 RCTs assessing the efficacy of probiotics for both the prevention of AAD and treatment of C difficile found a pooled relative risk (RR) of 0.43 for AAD in the patients taking probiotics.⁶ However, many of the studies included in that meta-analysis were small. As a result, in 2010, the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA) recommended against the use of probiotics for the prevention of primary C difficile infection, citing a lack of high-quality evidence.⁷

Nonetheless, that same year, 98% of gastroenterologists surveyed expressed a belief that probiotics had a role in the treatment of GI illness.⁸ And in 2011, the Third Yale Working Group on Probiotic Use published recommendations for probiotic use based on expert opinion.⁹ The meta-analysis detailed in this PURL, which included more than 30 trials published since the 2006 meta-analysis, addressed the efficacy of probiotics for prevention and treatment of AAD.

STUDY SUMMARY
Probiotics significantly reduce AAD
Hempel et al reviewed 82 studies and pooled data from 63 RCTs (N = 11,811) to identify the RR of AAD among patients who received probiotics during antibiotic treatment, compared with those who received no probiotics or were given a placebo.¹ The studies encompassed a variety of antibiotics, taken alone or in combination, and several probiotics, including Lactobacillus, Bifidobacterium, Saccharomyces, and some combinations.

The outcome: The pooled RR for AAD in the probiotics groups was 0.58, with a number needed to treat of 13. Although the authors reported that the overall quality of the included trials was poor, a sensitivity analysis of the higher-quality studies yielded similar results.

Subgroup analyses by type of probiotic and duration of antibiotic treatment were also consistent with the overall pooled RR. In subgroup analysis by age, a similar decrease in AAD was found among the youngest patients (ages 0 to 17) and those between the ages of 17 and 65. Among patients older than 65—for whom there were just three studies—a nonsignificant decrease in risk was found. Twenty-three of the studies assessed adverse outcomes, of which none were reported.

WHAT'S NEW
A reason to pair antibiotics and probiotics
This meta-analysis reached a similar conclusion to the 2006 meta-analysis: Probiotics appear to be effective in preventing and treating AAD in children and adults receiving a wide variety of antibiotics for a number of conditions. The results were also consistent with those of a new meta-analysis that looked specifically at one pathogen—and found a reduction of 66% in C difficile–associated diarrhea in patients taking probiotics with their antibiotics.¹⁰

CAVEATS
Limited data on the safety

of probiotics exist
There was some heterogeneity among the studies in the meta-analysis by Hempel et al,¹ and some of the studies were of poor quality. Because of this, the authors used subgroup and sensitivity analysis, which supported their initial conclusion.

Probiotics have generally been considered safe; however, there have been rare reports of sepsis and fungemia associated with probiotic use, especially in immunosuppressed patients.¹ Fifty-nine of the included studies did not assess adverse events, which limited the ability of this meta-analysis to assess safety.¹ Patients taking probiotics should be monitored for adverse effects.

CHALLENGES TO IMPLEMENTATION
Lack of guidance on dosing and duration
Since probiotics are considered food supplements, health insurance will not cover the cost (which will likely be more than $20 per month). No single probiotic strain has high-quality evidence; however, most of the RCTs included in the meta-analysis used combinations of Lactobacillus species, which are usually found in OTC antidiarrheal probiotic supplements. No standard dose exists, but dose ranges in RCTs are 107 to 1010 colony-forming units per capsule (taken one to three times daily);¹ however, product labels have variable accuracy.¹¹ The duration of treatment ranges from one to three weeks—or as long as the patient continues to take antibiotics. .

REFERENCES
1. Hempel S, Newberry S, Maher A, et al. Probiotics for the prevention and treatment of antibiotic-associated diarrhea. JAMA. 2012; 307:1959-1969.

2. McFarland LV. Antibiotic-associated diarrhea: epidemiology, trends and treatment. Future Microbiol. 2008;3:563-578.

3. Pepin J, Valiquette L, Cossette B. Mortality attributable to nosocomial Clostridium difficile–associated disease during an epidemic caused by a hypervirulent strain in Quebec. CMAJ. 2005;173:1037-1042.

4. Perry A, Dellon E, Lund J, et al. Burden of gastrointestinal disease in the United States: 2012 Update. Gastroenterology. 2012;143: 1179-1187.

5. Dubberke E, Wertheimer A. A review of current literature on the economic burden of Clostridium difficile infection. Infect Control Hosp Epidemiol. 2009;30:57-66.

6. McFarland L. Meta-analysis of probiotics for the prevention of antibiotic associated diarrhea and the treatment of Clostridium difficile disease. Am J Gastroenterol. 2006;101:

812-822.

7. Cohen S, Gerding D, Johnson S, et al. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America and the Infectious Diseases Society of America. Infect Control Hosp Epidemiol. 2010;31: 431-455.

8. Williams M, Ha C, Ciorba M. Probiotics as therapy in gastroenterology. J Clin Gastroenterol. 2010;44:631-636.

9. Floch M, Walker A, Madsne K, et al. Recommendations for probiotic use—2011 update. J Clin Gastroenterol. 2011;45(suppl):S168-S171.

10. Johnston BC, Ma SS, Goldenberg JZ, et al. Probiotics for the prevention of Clostridium difficile–associated diarrhea: a systematic review and meta-analysis. Ann Intern Med. 2012;157:878-888.

11. Hamilton-Miller J, Shah S. Deficiencies in microbiological quality and labeling of probiotic supplements. Int J Food Microbiol. 2002; 72:175-176.

Acknowledgement
The PURLs Surveillance System was developed with support from 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 © 2012. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2012;61:673-674.

PRACTICE CHANGER
Recommend that patients taking antibiotics also take probiotics, which have been found to be effective both for the prevention and treatment of antibiotic-associated diarrhea (AAD).¹

STRENGTH OF

RECOMMENDATION
A: Based on a systematic review and meta-analysis of randomized controlled trials (RCTs).

ILLUSTRATIVE CASE
When you prescribe an antibiotic for a 45-year-old patient with Helicobacter pylori, he worries that the medication will cause diarrhea. Should you recommend that he take probiotics?

More than a third of patients taking antibiotics develop AAD,² and in 17% of cases, AAD is fatal.^3,4 Although the diarrhea may be the result of increased gastrointestinal (GI) motility in some cases, a disruption of the GI flora that normally acts as a barrier to infection and aids in the digestion of carbohydrates is a far more common cause.

Morbidity and mortality are high
AAD is associated with several pathogens, including Clostridium difficile, Clostridium perfringens, Klebsiella oxytoca, and Staphylococcus aureus,² and varies widely in severity. Pseudomembranous colitis secondary to C difficile is the main cause of AAD-related mortality, which more than doubled from 2002 to 2009.^3,4 C difficile infections cost the US health care system up to $1.3 billion annually.⁵ With such high rates of morbidity and mortality and high health care costs associated with AAD, even a small reduction in the number of cases would have a big impact.

Probiotics replenish the natural GI flora with nonpathogenic organisms. A 2006 meta-analysis of 31 RCTs assessing the efficacy of probiotics for both the prevention of AAD and treatment of C difficile found a pooled relative risk (RR) of 0.43 for AAD in the patients taking probiotics.⁶ However, many of the studies included in that meta-analysis were small. As a result, in 2010, the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA) recommended against the use of probiotics for the prevention of primary C difficile infection, citing a lack of high-quality evidence.⁷

Nonetheless, that same year, 98% of gastroenterologists surveyed expressed a belief that probiotics had a role in the treatment of GI illness.⁸ And in 2011, the Third Yale Working Group on Probiotic Use published recommendations for probiotic use based on expert opinion.⁹ The meta-analysis detailed in this PURL, which included more than 30 trials published since the 2006 meta-analysis, addressed the efficacy of probiotics for prevention and treatment of AAD.

STUDY SUMMARY
Probiotics significantly reduce AAD
Hempel et al reviewed 82 studies and pooled data from 63 RCTs (N = 11,811) to identify the RR of AAD among patients who received probiotics during antibiotic treatment, compared with those who received no probiotics or were given a placebo.¹ The studies encompassed a variety of antibiotics, taken alone or in combination, and several probiotics, including Lactobacillus, Bifidobacterium, Saccharomyces, and some combinations.

The outcome: The pooled RR for AAD in the probiotics groups was 0.58, with a number needed to treat of 13. Although the authors reported that the overall quality of the included trials was poor, a sensitivity analysis of the higher-quality studies yielded similar results.

Subgroup analyses by type of probiotic and duration of antibiotic treatment were also consistent with the overall pooled RR. In subgroup analysis by age, a similar decrease in AAD was found among the youngest patients (ages 0 to 17) and those between the ages of 17 and 65. Among patients older than 65—for whom there were just three studies—a nonsignificant decrease in risk was found. Twenty-three of the studies assessed adverse outcomes, of which none were reported.

WHAT'S NEW
A reason to pair antibiotics and probiotics
This meta-analysis reached a similar conclusion to the 2006 meta-analysis: Probiotics appear to be effective in preventing and treating AAD in children and adults receiving a wide variety of antibiotics for a number of conditions. The results were also consistent with those of a new meta-analysis that looked specifically at one pathogen—and found a reduction of 66% in C difficile–associated diarrhea in patients taking probiotics with their antibiotics.¹⁰

CAVEATS
Limited data on the safety

of probiotics exist
There was some heterogeneity among the studies in the meta-analysis by Hempel et al,¹ and some of the studies were of poor quality. Because of this, the authors used subgroup and sensitivity analysis, which supported their initial conclusion.

Probiotics have generally been considered safe; however, there have been rare reports of sepsis and fungemia associated with probiotic use, especially in immunosuppressed patients.¹ Fifty-nine of the included studies did not assess adverse events, which limited the ability of this meta-analysis to assess safety.¹ Patients taking probiotics should be monitored for adverse effects.

CHALLENGES TO IMPLEMENTATION
Lack of guidance on dosing and duration
Since probiotics are considered food supplements, health insurance will not cover the cost (which will likely be more than $20 per month). No single probiotic strain has high-quality evidence; however, most of the RCTs included in the meta-analysis used combinations of Lactobacillus species, which are usually found in OTC antidiarrheal probiotic supplements. No standard dose exists, but dose ranges in RCTs are 107 to 1010 colony-forming units per capsule (taken one to three times daily);¹ however, product labels have variable accuracy.¹¹ The duration of treatment ranges from one to three weeks—or as long as the patient continues to take antibiotics. .

REFERENCES
1. Hempel S, Newberry S, Maher A, et al. Probiotics for the prevention and treatment of antibiotic-associated diarrhea. JAMA. 2012; 307:1959-1969.

2. McFarland LV. Antibiotic-associated diarrhea: epidemiology, trends and treatment. Future Microbiol. 2008;3:563-578.

3. Pepin J, Valiquette L, Cossette B. Mortality attributable to nosocomial Clostridium difficile–associated disease during an epidemic caused by a hypervirulent strain in Quebec. CMAJ. 2005;173:1037-1042.

4. Perry A, Dellon E, Lund J, et al. Burden of gastrointestinal disease in the United States: 2012 Update. Gastroenterology. 2012;143: 1179-1187.

5. Dubberke E, Wertheimer A. A review of current literature on the economic burden of Clostridium difficile infection. Infect Control Hosp Epidemiol. 2009;30:57-66.

6. McFarland L. Meta-analysis of probiotics for the prevention of antibiotic associated diarrhea and the treatment of Clostridium difficile disease. Am J Gastroenterol. 2006;101:

812-822.

7. Cohen S, Gerding D, Johnson S, et al. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America and the Infectious Diseases Society of America. Infect Control Hosp Epidemiol. 2010;31: 431-455.

8. Williams M, Ha C, Ciorba M. Probiotics as therapy in gastroenterology. J Clin Gastroenterol. 2010;44:631-636.

9. Floch M, Walker A, Madsne K, et al. Recommendations for probiotic use—2011 update. J Clin Gastroenterol. 2011;45(suppl):S168-S171.

10. Johnston BC, Ma SS, Goldenberg JZ, et al. Probiotics for the prevention of Clostridium difficile–associated diarrhea: a systematic review and meta-analysis. Ann Intern Med. 2012;157:878-888.

11. Hamilton-Miller J, Shah S. Deficiencies in microbiological quality and labeling of probiotic supplements. Int J Food Microbiol. 2002; 72:175-176.

Acknowledgement
The PURLs Surveillance System was developed with support from 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 © 2012. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2012;61:673-674.

ILLUSTRATIVE CASES

• A 60-year-old man has struggled to get his BP under control despite the use of 3 anti-hypertensives. Is there anything you can recommend to improve his BP control and lower his cardiovascular risk?
• You prescribe hydrochlorothiazide for a 55-year-old woman with newly diagnosed hypertension. What can you tell her about how to take the medication to maximize its beneficial effects?

Management of hypertension often centers around BP measurements taken in a doctor’s office during the day, although both BP and metabolism fluctuate with circadian rhythms. Most people experience an increase in pressure during the day, with peaks in the morning and evening, followed by a decline in BP while they sleep at night.³

The focus belongs on nighttime BP
Sleeping BP is getting considerable attention, particularly the phenomenon of nondipping. Commonly defined as a <10% decline in systolic pressure during sleep, nondipping is associated with an increased risk of cardiovascular events, such as heart attack and stroke.⁴ What’s more, mean BP during the night is a better predictor of cardiovascular disease (CVD) risk than BP while the patient is awake.^5,6

Evidence suggests that taking an anti-hypertensive medication at night increases its therapeutic effect,⁷ yet most patients take it in the morning.⁸ The study detailed in this PURL was designed to investigate whether bedtime dosing significantly affects BP control and CVD risk.

STUDY SUMMARY: Bedtime dosing benefits patients, and there’s no downside

The MAPEC study was an open-label RCT conducted at a single center in Spain.¹ Patients were enrolled if they had a diagnosis of either untreated hypertension (based on ambulatory BP monitoring [ABPM] criteria) or resistant hypertension (uncontrolled on ≥3 optimally dosed antihypertensive medications). Exclusion criteria included pregnancy, a history of drug/alcohol abuse, night shift work, acquired immune deficiency syndrome, type 1 diabetes, secondary hypertension, and a previous CVD diagnosis.

Patients were randomly assigned to one of 2 time-of-day dosing groups: morning dosing of all their BP medications (n=1109) or dosing of ≥1 BP medications at bedtime (n=1092). ABPM—in which patients wore a monitor that recorded their BP every 20 minutes during the day and every 30 minutes at night for 48 hours—was conducted once a year, or more frequently when medication adjustments occurred. The use of a specific drug was not required, but physicians were instructed to adjust medications according to a study-specific ABPM protocol.

Patients were followed for a mean of 5.6 years for the endpoints of CVD events and mortality. These endpoints were assessed by researchers blinded to patients’ treatment assignment.

At baseline, the 2 groups were similar in age (mean of 55 years), percentage of men (48%), presence of comorbidities, and baseline clinic and ambulatory BP. Throughout the study, patients in the bedtime dosing group had lower mean asleep systolic and diastolic BP, a lower prevalence of a non-dipping pattern, and a higher prevalence of controlled ambulatory BP. The bedtime group also had a lower risk of total CVD events (relative risk [RR]=0.39; 95% confidence interval [CI], 0.29-0.51; P<.001) and major CVD events (RR=0.33; 95% CI, 0.19-0.55; P<.001), and fewer overall deaths (4.16/1000 vs 2.11/1000 patient-years; P=.008) (TABLE). To prevent one CVD event, 63 patients would need to take their BP medication at bedtime instead of in the morning for one year. To prevent one death, 488 patient would need to adhere to the nighttime schedule for one year.

A subgroup analysis of patients with type 2 diabetes (n=448)² had similar results: For this population, too, bedtime dosing led to lower asleep BP, a lower prevalence of a non-dipping pattern, and a higher prevalence of controlled ambulatory BP, as well as a lower risk of total CVD events, major CVD events, and CVD-related death. The differences persisted after correction for the use of statins and aspirin. Among those in this subgroup analysis, 29 patients would need to take their BP medications at bedtime for one year to prevent one CVD event, and 263 patients would need to be treated for one year to prevent one death.

TABLE
Dosing of BP meds: A look at outcomes

WHAT’S NEW: Advantages of preventing nondipping are clearly established

We’ve known that a nondipping pattern is associated with higher cardiovascular risks and that taking antihypertensives at bedtime decreases the prevalence of nondipping patterns. The MAPEC study, however, is the first prospective trial to show that bedtime dosing of BP medications lowers the risk of CVD events and death.

CAVEATS: Methodology, non-US guidelines raise questions about applicability here

MAPEC was an open-label study, meaning that the physicians adjusting BP medications were aware of the treatment groups to which their patients were allocated. Physicians were given guidelines for the titration of medications, but it is unclear whether they treated patients in both treatment groups identically. Patients were also aware of their treatment group, which creates the potential for bias if one group adhered to their medications more closely than the other.

The study was a single-center trial conducted in Spain, which may limit its generalizability to the United States. Notably, Spain’s medication guidelines differ from ours, with angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, and calcium channel blockers as first-line medications and hydrochlorothiazide as a second-line option.

While ABPM appears to be a better indicator of CVD risk compared with clinic BP monitoring, most US physicians still rely on readings taken in their office for diagnosing and managing hypertension. How ambulatory BP translates to clinic BP is somewhat unclear.

CHALLENGES TO IMPLEMENTATION: Some patients and providers may resist the switch

We see few challenges to implementing bedtime dosing of BP medications for patients with uncontrolled hypertension. It is possible, however, that patients who have a long-standing routine of taking their medications in the morning may be resistant to change. Also, pharmacists and nurses, as well as some physicians, may continue recommending morning dosing, which could be confusing for patients.

Acknowledgement

The PURLs Surveillance System is 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.

ILLUSTRATIVE CASES

• A 60-year-old man has struggled to get his BP under control despite the use of 3 anti-hypertensives. Is there anything you can recommend to improve his BP control and lower his cardiovascular risk?
• You prescribe hydrochlorothiazide for a 55-year-old woman with newly diagnosed hypertension. What can you tell her about how to take the medication to maximize its beneficial effects?

Management of hypertension often centers around BP measurements taken in a doctor’s office during the day, although both BP and metabolism fluctuate with circadian rhythms. Most people experience an increase in pressure during the day, with peaks in the morning and evening, followed by a decline in BP while they sleep at night.³

The focus belongs on nighttime BP
Sleeping BP is getting considerable attention, particularly the phenomenon of nondipping. Commonly defined as a <10% decline in systolic pressure during sleep, nondipping is associated with an increased risk of cardiovascular events, such as heart attack and stroke.⁴ What’s more, mean BP during the night is a better predictor of cardiovascular disease (CVD) risk than BP while the patient is awake.^5,6

Evidence suggests that taking an anti-hypertensive medication at night increases its therapeutic effect,⁷ yet most patients take it in the morning.⁸ The study detailed in this PURL was designed to investigate whether bedtime dosing significantly affects BP control and CVD risk.

STUDY SUMMARY: Bedtime dosing benefits patients, and there’s no downside

The MAPEC study was an open-label RCT conducted at a single center in Spain.¹ Patients were enrolled if they had a diagnosis of either untreated hypertension (based on ambulatory BP monitoring [ABPM] criteria) or resistant hypertension (uncontrolled on ≥3 optimally dosed antihypertensive medications). Exclusion criteria included pregnancy, a history of drug/alcohol abuse, night shift work, acquired immune deficiency syndrome, type 1 diabetes, secondary hypertension, and a previous CVD diagnosis.

Patients were randomly assigned to one of 2 time-of-day dosing groups: morning dosing of all their BP medications (n=1109) or dosing of ≥1 BP medications at bedtime (n=1092). ABPM—in which patients wore a monitor that recorded their BP every 20 minutes during the day and every 30 minutes at night for 48 hours—was conducted once a year, or more frequently when medication adjustments occurred. The use of a specific drug was not required, but physicians were instructed to adjust medications according to a study-specific ABPM protocol.

Patients were followed for a mean of 5.6 years for the endpoints of CVD events and mortality. These endpoints were assessed by researchers blinded to patients’ treatment assignment.

At baseline, the 2 groups were similar in age (mean of 55 years), percentage of men (48%), presence of comorbidities, and baseline clinic and ambulatory BP. Throughout the study, patients in the bedtime dosing group had lower mean asleep systolic and diastolic BP, a lower prevalence of a non-dipping pattern, and a higher prevalence of controlled ambulatory BP. The bedtime group also had a lower risk of total CVD events (relative risk [RR]=0.39; 95% confidence interval [CI], 0.29-0.51; P<.001) and major CVD events (RR=0.33; 95% CI, 0.19-0.55; P<.001), and fewer overall deaths (4.16/1000 vs 2.11/1000 patient-years; P=.008) (TABLE). To prevent one CVD event, 63 patients would need to take their BP medication at bedtime instead of in the morning for one year. To prevent one death, 488 patient would need to adhere to the nighttime schedule for one year.

A subgroup analysis of patients with type 2 diabetes (n=448)² had similar results: For this population, too, bedtime dosing led to lower asleep BP, a lower prevalence of a non-dipping pattern, and a higher prevalence of controlled ambulatory BP, as well as a lower risk of total CVD events, major CVD events, and CVD-related death. The differences persisted after correction for the use of statins and aspirin. Among those in this subgroup analysis, 29 patients would need to take their BP medications at bedtime for one year to prevent one CVD event, and 263 patients would need to be treated for one year to prevent one death.

TABLE
Dosing of BP meds: A look at outcomes

WHAT’S NEW: Advantages of preventing nondipping are clearly established

We’ve known that a nondipping pattern is associated with higher cardiovascular risks and that taking antihypertensives at bedtime decreases the prevalence of nondipping patterns. The MAPEC study, however, is the first prospective trial to show that bedtime dosing of BP medications lowers the risk of CVD events and death.

CAVEATS: Methodology, non-US guidelines raise questions about applicability here

MAPEC was an open-label study, meaning that the physicians adjusting BP medications were aware of the treatment groups to which their patients were allocated. Physicians were given guidelines for the titration of medications, but it is unclear whether they treated patients in both treatment groups identically. Patients were also aware of their treatment group, which creates the potential for bias if one group adhered to their medications more closely than the other.

The study was a single-center trial conducted in Spain, which may limit its generalizability to the United States. Notably, Spain’s medication guidelines differ from ours, with angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, and calcium channel blockers as first-line medications and hydrochlorothiazide as a second-line option.

While ABPM appears to be a better indicator of CVD risk compared with clinic BP monitoring, most US physicians still rely on readings taken in their office for diagnosing and managing hypertension. How ambulatory BP translates to clinic BP is somewhat unclear.

CHALLENGES TO IMPLEMENTATION: Some patients and providers may resist the switch

We see few challenges to implementing bedtime dosing of BP medications for patients with uncontrolled hypertension. It is possible, however, that patients who have a long-standing routine of taking their medications in the morning may be resistant to change. Also, pharmacists and nurses, as well as some physicians, may continue recommending morning dosing, which could be confusing for patients.

Acknowledgement

The PURLs Surveillance System is 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.

ILLUSTRATIVE CASES

• A 60-year-old man has struggled to get his BP under control despite the use of 3 anti-hypertensives. Is there anything you can recommend to improve his BP control and lower his cardiovascular risk?
• You prescribe hydrochlorothiazide for a 55-year-old woman with newly diagnosed hypertension. What can you tell her about how to take the medication to maximize its beneficial effects?

Management of hypertension often centers around BP measurements taken in a doctor’s office during the day, although both BP and metabolism fluctuate with circadian rhythms. Most people experience an increase in pressure during the day, with peaks in the morning and evening, followed by a decline in BP while they sleep at night.³

The focus belongs on nighttime BP
Sleeping BP is getting considerable attention, particularly the phenomenon of nondipping. Commonly defined as a <10% decline in systolic pressure during sleep, nondipping is associated with an increased risk of cardiovascular events, such as heart attack and stroke.⁴ What’s more, mean BP during the night is a better predictor of cardiovascular disease (CVD) risk than BP while the patient is awake.^5,6

Evidence suggests that taking an anti-hypertensive medication at night increases its therapeutic effect,⁷ yet most patients take it in the morning.⁸ The study detailed in this PURL was designed to investigate whether bedtime dosing significantly affects BP control and CVD risk.

STUDY SUMMARY: Bedtime dosing benefits patients, and there’s no downside

The MAPEC study was an open-label RCT conducted at a single center in Spain.¹ Patients were enrolled if they had a diagnosis of either untreated hypertension (based on ambulatory BP monitoring [ABPM] criteria) or resistant hypertension (uncontrolled on ≥3 optimally dosed antihypertensive medications). Exclusion criteria included pregnancy, a history of drug/alcohol abuse, night shift work, acquired immune deficiency syndrome, type 1 diabetes, secondary hypertension, and a previous CVD diagnosis.

Patients were randomly assigned to one of 2 time-of-day dosing groups: morning dosing of all their BP medications (n=1109) or dosing of ≥1 BP medications at bedtime (n=1092). ABPM—in which patients wore a monitor that recorded their BP every 20 minutes during the day and every 30 minutes at night for 48 hours—was conducted once a year, or more frequently when medication adjustments occurred. The use of a specific drug was not required, but physicians were instructed to adjust medications according to a study-specific ABPM protocol.

Patients were followed for a mean of 5.6 years for the endpoints of CVD events and mortality. These endpoints were assessed by researchers blinded to patients’ treatment assignment.

At baseline, the 2 groups were similar in age (mean of 55 years), percentage of men (48%), presence of comorbidities, and baseline clinic and ambulatory BP. Throughout the study, patients in the bedtime dosing group had lower mean asleep systolic and diastolic BP, a lower prevalence of a non-dipping pattern, and a higher prevalence of controlled ambulatory BP. The bedtime group also had a lower risk of total CVD events (relative risk [RR]=0.39; 95% confidence interval [CI], 0.29-0.51; P<.001) and major CVD events (RR=0.33; 95% CI, 0.19-0.55; P<.001), and fewer overall deaths (4.16/1000 vs 2.11/1000 patient-years; P=.008) (TABLE). To prevent one CVD event, 63 patients would need to take their BP medication at bedtime instead of in the morning for one year. To prevent one death, 488 patient would need to adhere to the nighttime schedule for one year.

A subgroup analysis of patients with type 2 diabetes (n=448)² had similar results: For this population, too, bedtime dosing led to lower asleep BP, a lower prevalence of a non-dipping pattern, and a higher prevalence of controlled ambulatory BP, as well as a lower risk of total CVD events, major CVD events, and CVD-related death. The differences persisted after correction for the use of statins and aspirin. Among those in this subgroup analysis, 29 patients would need to take their BP medications at bedtime for one year to prevent one CVD event, and 263 patients would need to be treated for one year to prevent one death.

TABLE
Dosing of BP meds: A look at outcomes

WHAT’S NEW: Advantages of preventing nondipping are clearly established

We’ve known that a nondipping pattern is associated with higher cardiovascular risks and that taking antihypertensives at bedtime decreases the prevalence of nondipping patterns. The MAPEC study, however, is the first prospective trial to show that bedtime dosing of BP medications lowers the risk of CVD events and death.

CAVEATS: Methodology, non-US guidelines raise questions about applicability here

MAPEC was an open-label study, meaning that the physicians adjusting BP medications were aware of the treatment groups to which their patients were allocated. Physicians were given guidelines for the titration of medications, but it is unclear whether they treated patients in both treatment groups identically. Patients were also aware of their treatment group, which creates the potential for bias if one group adhered to their medications more closely than the other.

The study was a single-center trial conducted in Spain, which may limit its generalizability to the United States. Notably, Spain’s medication guidelines differ from ours, with angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, and calcium channel blockers as first-line medications and hydrochlorothiazide as a second-line option.

While ABPM appears to be a better indicator of CVD risk compared with clinic BP monitoring, most US physicians still rely on readings taken in their office for diagnosing and managing hypertension. How ambulatory BP translates to clinic BP is somewhat unclear.

CHALLENGES TO IMPLEMENTATION: Some patients and providers may resist the switch

We see few challenges to implementing bedtime dosing of BP medications for patients with uncontrolled hypertension. It is possible, however, that patients who have a long-standing routine of taking their medications in the morning may be resistant to change. Also, pharmacists and nurses, as well as some physicians, may continue recommending morning dosing, which could be confusing for patients.

Acknowledgement

The PURLs Surveillance System is 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.

ILLUSTRATIVE CASE

A 75-year-old man with persistent atrial fibrillation and diabetes comes to your office for a check of his international normalized ratio (INR). It has been hard to keep his INR within the normal range of 2 to 3 in recent months, and today is no different: The patient’s INR is 1.7, although he insists he has been compliant with his warfarin regimen and has had no change in diet or other medications. What other anticoagulation options can you offer him?

Patients with atrial fibrillation have a 3% to 8% annual risk of stroke.² Both adjusted-dose warfarin and antiplatelet agents such as aspirin have been shown to be effective at reducing this risk, although warfarin is significantly more effective.³

Those who have atrial fibrillation and a previous history of thromboembolism or rheumatic mitral stenosis or more than one moderate risk factor (age ≥75 years, hypertension, heart failure, impaired left ventricular systolic function, or diabetes) have the highest stroke risk. The American College of Cardiology/American Heart Association Task Force/ European Society of Cardiology (ACC/AHA/ ESC) 2006 guidelines for the management of atrial fibrillation recommend chronic anticoagulation with an oral vitamin K antagonist, such as warfarin, for these high-risk patients.⁴

Warfarin therapy is challenging
We have all experienced the frustrations of maintaining our patients on warfarin at a therapeutic INR; the average patient is within this range only about 67% of the time, although this varies dramatically from patient to patient.⁵

Many of our patients have experienced the inconvenience and cost of repeated monitoring, as well as the morbidity associated with both major and minor bleeding related to warfarin use. And there are many potential interactions between warfarin and foods or other drugs.

Is the new oral anticoagulant a better bet?
There are anticoagulants that do not require monitoring (eg, enoxaparin), but few patients are willing to undergo daily subcutaneous injections, and the cost is often prohibitive. Now there is another alternative.

Dabigatran (Pradaxa), an oral direct thrombin inhibitor, was approved by the US Food and Drug Administration in October 2010 for the prevention of stroke and systemic embolism in patients with atrial fibrillation.⁶ Dabigatran is administered twice daily in a fixed dose. Because it has a relatively short half-life (12-17 hours), it does not require INR monitoring. Dabigatran has no known interactions with foods and minimal interactions with other medications. Its value as a warfarin alternative for patients with atrial fibrillation was addressed in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) study detailed below.

STUDY SUMMARY: At higher dose, dabigatran prevents more strokes than warfarin

RE-LY included 18,113 patients from 951 facilities in 44 countries. To be eligible for the study, patients had to have atrial fibrillation documented on an electrocardiogram and at least one additional risk factor for stroke.

Participants were randomized into one of 3 groups: dabigatran 110 mg twice daily, dabigatran 150 mg twice daily (both administered in a blinded fashion), or warfarin (administered in an unblinded fashion and dosed to maintain an INR between 2 and 3). Baseline characteristics, such as age, sex, and CHADS₂ (congestive heart failure, hypertension, age, diabetes, prior stroke) score, were similar across all 3 groups. The median duration of follow-up was 2 years, and complete follow-up occurred in 99.9% of participants.

The primary outcome of the study was stroke or systemic embolism. The primary safety outcome was major hemorrhage, defined as a reduction in hemoglobin of ≥2 g/dL, transfusion of ≥2 units of blood, or symptomatic bleeding in a critical area/organ. Other outcomes were death, myocardial infarction (MI), pulmonary embolism, transient ischemic attack, and hospitalization.

For the primary outcome of prevention of stroke or systemic embolism, the 150-mg dose of dabigatran was superior to warfarin (1.11% vs 1.69% per year, relative risk [RR], 0.66; 95% confidence interval [CI], 0.53-0.82; P<.001 for superiority). The major bleeding rates were similar for dabigatran 150 mg and warfarin, although major gastrointestinal bleeding rates were significantly higher with this dose of dabigatran compared with warfarin (TABLE). Minor bleeding was more common in the warfarin group (16.37% vs 14.84%; RR, 0.91; 95% CI, 0.85-0.97; P=.005).

The 110-mg dose of dabigatran (which is not available in the United States) was neither inferior nor superior to warfarin for the prevention of stroke or systemic embolism. This dose of dabigatran had a lower risk of major bleeding compared with warfarin.

TABLE
Dabigatran vs warfarin: A look at the evidence¹

Mortality rates are similar
Rates of death from any cause were similar among the 3 treatment groups. The rates of hemorrhagic stroke were lower in both dabigatran groups compared with the warfarin group, while rates of MI were lower in the warfarin group than in either of the dabigatran groups.

Dyspepsia was the only other adverse effect that was significantly more common among dabigatran users vs warfarin users. Rates of hepatotoxicity, which was a problem wiThearlier oral direct thrombin inhibitors, were similar for both drugs. Multiple subgroup analyses revealed no significant interaction between the treatment effect of dabigatran and variables such as sex, body mass index, creatinine clearance, CHADS₂ score, aspirin use, or previous long-term use of a vitamin K antagonist.

WHAT’S NEW: This easier-to-use oral anticoagulant is a viable option

Dabigatran gives physicians and patients with atrial fibrillation an option that is more convenient than warfarin for stroke prevention. Its 150-mg dose is more effective in preventing stroke compared with warfarin, and comparable in terms of bleeding risk.

CAVEATS: Unknown long-term effects, potential for bias

The median follow-up in the RE-LY study was 2 years. Longer-term efficacy and safety data may differ from the initial results.

The trial was funded by Boehringer Ingelheim, the manufacturer of dabigatran (Pradaxa). However, study coordination, data management, and analysis were performed independently by the Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada.

Patients taking dabigatran received the medication in a blinded fashion, but the warfarin group could not be blinded because of the need for INR monitoring and dosage adjustments. To decrease potential bias, the outcome events were assessed by 2 independent investigators who were blinded to the treatment assignments.

CHALLENGES TO IMPLEMENTATION: Cost of dabigatran may be a barrier

The wholesale price of dabigatran, as quoted by Boehringer Ingelheim, is $6.75 per day; the retail price for a 30-day supply is approximately $235, according to drugstore.com, Walgreens, and Walmart). In comparison, a one-month supply of warfarin is about $15. Out-of-pocket costs for many patients will likely be high until dabigatran is added to insurers’ formularies. When costs for monitoring and hospitalizations or treatment for complications associated with warfarin are factored in, however, dabigatran is cost effective, a recent study indicates.⁷

Acknowledgement

The PURLs Surveillance System is 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.

Click here to view PURL METHODOLOGY

ILLUSTRATIVE CASE

A 75-year-old man with persistent atrial fibrillation and diabetes comes to your office for a check of his international normalized ratio (INR). It has been hard to keep his INR within the normal range of 2 to 3 in recent months, and today is no different: The patient’s INR is 1.7, although he insists he has been compliant with his warfarin regimen and has had no change in diet or other medications. What other anticoagulation options can you offer him?

Patients with atrial fibrillation have a 3% to 8% annual risk of stroke.² Both adjusted-dose warfarin and antiplatelet agents such as aspirin have been shown to be effective at reducing this risk, although warfarin is significantly more effective.³

Those who have atrial fibrillation and a previous history of thromboembolism or rheumatic mitral stenosis or more than one moderate risk factor (age ≥75 years, hypertension, heart failure, impaired left ventricular systolic function, or diabetes) have the highest stroke risk. The American College of Cardiology/American Heart Association Task Force/ European Society of Cardiology (ACC/AHA/ ESC) 2006 guidelines for the management of atrial fibrillation recommend chronic anticoagulation with an oral vitamin K antagonist, such as warfarin, for these high-risk patients.⁴

Warfarin therapy is challenging
We have all experienced the frustrations of maintaining our patients on warfarin at a therapeutic INR; the average patient is within this range only about 67% of the time, although this varies dramatically from patient to patient.⁵

Many of our patients have experienced the inconvenience and cost of repeated monitoring, as well as the morbidity associated with both major and minor bleeding related to warfarin use. And there are many potential interactions between warfarin and foods or other drugs.

Is the new oral anticoagulant a better bet?
There are anticoagulants that do not require monitoring (eg, enoxaparin), but few patients are willing to undergo daily subcutaneous injections, and the cost is often prohibitive. Now there is another alternative.

Dabigatran (Pradaxa), an oral direct thrombin inhibitor, was approved by the US Food and Drug Administration in October 2010 for the prevention of stroke and systemic embolism in patients with atrial fibrillation.⁶ Dabigatran is administered twice daily in a fixed dose. Because it has a relatively short half-life (12-17 hours), it does not require INR monitoring. Dabigatran has no known interactions with foods and minimal interactions with other medications. Its value as a warfarin alternative for patients with atrial fibrillation was addressed in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) study detailed below.

STUDY SUMMARY: At higher dose, dabigatran prevents more strokes than warfarin

RE-LY included 18,113 patients from 951 facilities in 44 countries. To be eligible for the study, patients had to have atrial fibrillation documented on an electrocardiogram and at least one additional risk factor for stroke.

Participants were randomized into one of 3 groups: dabigatran 110 mg twice daily, dabigatran 150 mg twice daily (both administered in a blinded fashion), or warfarin (administered in an unblinded fashion and dosed to maintain an INR between 2 and 3). Baseline characteristics, such as age, sex, and CHADS₂ (congestive heart failure, hypertension, age, diabetes, prior stroke) score, were similar across all 3 groups. The median duration of follow-up was 2 years, and complete follow-up occurred in 99.9% of participants.

The primary outcome of the study was stroke or systemic embolism. The primary safety outcome was major hemorrhage, defined as a reduction in hemoglobin of ≥2 g/dL, transfusion of ≥2 units of blood, or symptomatic bleeding in a critical area/organ. Other outcomes were death, myocardial infarction (MI), pulmonary embolism, transient ischemic attack, and hospitalization.

For the primary outcome of prevention of stroke or systemic embolism, the 150-mg dose of dabigatran was superior to warfarin (1.11% vs 1.69% per year, relative risk [RR], 0.66; 95% confidence interval [CI], 0.53-0.82; P<.001 for superiority). The major bleeding rates were similar for dabigatran 150 mg and warfarin, although major gastrointestinal bleeding rates were significantly higher with this dose of dabigatran compared with warfarin (TABLE). Minor bleeding was more common in the warfarin group (16.37% vs 14.84%; RR, 0.91; 95% CI, 0.85-0.97; P=.005).

The 110-mg dose of dabigatran (which is not available in the United States) was neither inferior nor superior to warfarin for the prevention of stroke or systemic embolism. This dose of dabigatran had a lower risk of major bleeding compared with warfarin.

TABLE
Dabigatran vs warfarin: A look at the evidence¹

Mortality rates are similar
Rates of death from any cause were similar among the 3 treatment groups. The rates of hemorrhagic stroke were lower in both dabigatran groups compared with the warfarin group, while rates of MI were lower in the warfarin group than in either of the dabigatran groups.

Dyspepsia was the only other adverse effect that was significantly more common among dabigatran users vs warfarin users. Rates of hepatotoxicity, which was a problem wiThearlier oral direct thrombin inhibitors, were similar for both drugs. Multiple subgroup analyses revealed no significant interaction between the treatment effect of dabigatran and variables such as sex, body mass index, creatinine clearance, CHADS₂ score, aspirin use, or previous long-term use of a vitamin K antagonist.

WHAT’S NEW: This easier-to-use oral anticoagulant is a viable option

Dabigatran gives physicians and patients with atrial fibrillation an option that is more convenient than warfarin for stroke prevention. Its 150-mg dose is more effective in preventing stroke compared with warfarin, and comparable in terms of bleeding risk.

CAVEATS: Unknown long-term effects, potential for bias

The median follow-up in the RE-LY study was 2 years. Longer-term efficacy and safety data may differ from the initial results.

The trial was funded by Boehringer Ingelheim, the manufacturer of dabigatran (Pradaxa). However, study coordination, data management, and analysis were performed independently by the Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada.

Patients taking dabigatran received the medication in a blinded fashion, but the warfarin group could not be blinded because of the need for INR monitoring and dosage adjustments. To decrease potential bias, the outcome events were assessed by 2 independent investigators who were blinded to the treatment assignments.

CHALLENGES TO IMPLEMENTATION: Cost of dabigatran may be a barrier

The wholesale price of dabigatran, as quoted by Boehringer Ingelheim, is $6.75 per day; the retail price for a 30-day supply is approximately $235, according to drugstore.com, Walgreens, and Walmart). In comparison, a one-month supply of warfarin is about $15. Out-of-pocket costs for many patients will likely be high until dabigatran is added to insurers’ formularies. When costs for monitoring and hospitalizations or treatment for complications associated with warfarin are factored in, however, dabigatran is cost effective, a recent study indicates.⁷

Acknowledgement

The PURLs Surveillance System is 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.

Click here to view PURL METHODOLOGY

ILLUSTRATIVE CASE

A 75-year-old man with persistent atrial fibrillation and diabetes comes to your office for a check of his international normalized ratio (INR). It has been hard to keep his INR within the normal range of 2 to 3 in recent months, and today is no different: The patient’s INR is 1.7, although he insists he has been compliant with his warfarin regimen and has had no change in diet or other medications. What other anticoagulation options can you offer him?

Patients with atrial fibrillation have a 3% to 8% annual risk of stroke.² Both adjusted-dose warfarin and antiplatelet agents such as aspirin have been shown to be effective at reducing this risk, although warfarin is significantly more effective.³

Those who have atrial fibrillation and a previous history of thromboembolism or rheumatic mitral stenosis or more than one moderate risk factor (age ≥75 years, hypertension, heart failure, impaired left ventricular systolic function, or diabetes) have the highest stroke risk. The American College of Cardiology/American Heart Association Task Force/ European Society of Cardiology (ACC/AHA/ ESC) 2006 guidelines for the management of atrial fibrillation recommend chronic anticoagulation with an oral vitamin K antagonist, such as warfarin, for these high-risk patients.⁴

Warfarin therapy is challenging
We have all experienced the frustrations of maintaining our patients on warfarin at a therapeutic INR; the average patient is within this range only about 67% of the time, although this varies dramatically from patient to patient.⁵

Many of our patients have experienced the inconvenience and cost of repeated monitoring, as well as the morbidity associated with both major and minor bleeding related to warfarin use. And there are many potential interactions between warfarin and foods or other drugs.

Is the new oral anticoagulant a better bet?
There are anticoagulants that do not require monitoring (eg, enoxaparin), but few patients are willing to undergo daily subcutaneous injections, and the cost is often prohibitive. Now there is another alternative.

Dabigatran (Pradaxa), an oral direct thrombin inhibitor, was approved by the US Food and Drug Administration in October 2010 for the prevention of stroke and systemic embolism in patients with atrial fibrillation.⁶ Dabigatran is administered twice daily in a fixed dose. Because it has a relatively short half-life (12-17 hours), it does not require INR monitoring. Dabigatran has no known interactions with foods and minimal interactions with other medications. Its value as a warfarin alternative for patients with atrial fibrillation was addressed in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) study detailed below.

STUDY SUMMARY: At higher dose, dabigatran prevents more strokes than warfarin

RE-LY included 18,113 patients from 951 facilities in 44 countries. To be eligible for the study, patients had to have atrial fibrillation documented on an electrocardiogram and at least one additional risk factor for stroke.

Participants were randomized into one of 3 groups: dabigatran 110 mg twice daily, dabigatran 150 mg twice daily (both administered in a blinded fashion), or warfarin (administered in an unblinded fashion and dosed to maintain an INR between 2 and 3). Baseline characteristics, such as age, sex, and CHADS₂ (congestive heart failure, hypertension, age, diabetes, prior stroke) score, were similar across all 3 groups. The median duration of follow-up was 2 years, and complete follow-up occurred in 99.9% of participants.

The primary outcome of the study was stroke or systemic embolism. The primary safety outcome was major hemorrhage, defined as a reduction in hemoglobin of ≥2 g/dL, transfusion of ≥2 units of blood, or symptomatic bleeding in a critical area/organ. Other outcomes were death, myocardial infarction (MI), pulmonary embolism, transient ischemic attack, and hospitalization.

For the primary outcome of prevention of stroke or systemic embolism, the 150-mg dose of dabigatran was superior to warfarin (1.11% vs 1.69% per year, relative risk [RR], 0.66; 95% confidence interval [CI], 0.53-0.82; P<.001 for superiority). The major bleeding rates were similar for dabigatran 150 mg and warfarin, although major gastrointestinal bleeding rates were significantly higher with this dose of dabigatran compared with warfarin (TABLE). Minor bleeding was more common in the warfarin group (16.37% vs 14.84%; RR, 0.91; 95% CI, 0.85-0.97; P=.005).

The 110-mg dose of dabigatran (which is not available in the United States) was neither inferior nor superior to warfarin for the prevention of stroke or systemic embolism. This dose of dabigatran had a lower risk of major bleeding compared with warfarin.

TABLE
Dabigatran vs warfarin: A look at the evidence¹

Mortality rates are similar
Rates of death from any cause were similar among the 3 treatment groups. The rates of hemorrhagic stroke were lower in both dabigatran groups compared with the warfarin group, while rates of MI were lower in the warfarin group than in either of the dabigatran groups.

Dyspepsia was the only other adverse effect that was significantly more common among dabigatran users vs warfarin users. Rates of hepatotoxicity, which was a problem wiThearlier oral direct thrombin inhibitors, were similar for both drugs. Multiple subgroup analyses revealed no significant interaction between the treatment effect of dabigatran and variables such as sex, body mass index, creatinine clearance, CHADS₂ score, aspirin use, or previous long-term use of a vitamin K antagonist.

WHAT’S NEW: This easier-to-use oral anticoagulant is a viable option

Dabigatran gives physicians and patients with atrial fibrillation an option that is more convenient than warfarin for stroke prevention. Its 150-mg dose is more effective in preventing stroke compared with warfarin, and comparable in terms of bleeding risk.

CAVEATS: Unknown long-term effects, potential for bias

The median follow-up in the RE-LY study was 2 years. Longer-term efficacy and safety data may differ from the initial results.

The trial was funded by Boehringer Ingelheim, the manufacturer of dabigatran (Pradaxa). However, study coordination, data management, and analysis were performed independently by the Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada.

Patients taking dabigatran received the medication in a blinded fashion, but the warfarin group could not be blinded because of the need for INR monitoring and dosage adjustments. To decrease potential bias, the outcome events were assessed by 2 independent investigators who were blinded to the treatment assignments.

CHALLENGES TO IMPLEMENTATION: Cost of dabigatran may be a barrier

The wholesale price of dabigatran, as quoted by Boehringer Ingelheim, is $6.75 per day; the retail price for a 30-day supply is approximately $235, according to drugstore.com, Walgreens, and Walmart). In comparison, a one-month supply of warfarin is about $15. Out-of-pocket costs for many patients will likely be high until dabigatran is added to insurers’ formularies. When costs for monitoring and hospitalizations or treatment for complications associated with warfarin are factored in, however, dabigatran is cost effective, a recent study indicates.⁷

Acknowledgement

The PURLs Surveillance System is 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.

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