Gary N. Asher, MD, MPH

PRACTICE CHANGER

Recommend American ginseng (1,000 mg bid) for four weeks to improve cancer-related fatigue in patients who are undergoing radiation or chemotherapy; no other treatment has been shown to be effective.¹

STRENGTH OF RECOMMENDATION

B: Based on a single well-done randomized controlled trial (RCT).¹

ILLUSTRATIVE CASE

A 54-year-old woman is receiving chemotherapy for adenocarcinoma of the right breast (T2N1M0) and has persistent, disabling fatigue. She has been unable to work or care for her family since starting chemotherapy. She says she gets enough sleep and denies being depressed or in pain. Lab testing for anemia and thyroid dysfunction is negative. Is there a safe and effective intervention?

On the next page: Study summary >>

Cancer-related fatigue is a common, distressing symptom that occurs in more than half of all patients undergoing chemotherapy and more than two-thirds of those receiving radiation therapy.² For many cancer survivors, fatigue can persist for five to 10 years after treatment.³

Because no treatments have proven effective, many clinicians and patients accept fatigue as inevitable. In RCTs, psychostimulants (eg, methylphenidate) and antidepressants (eg, donepezil and paroxetine) have not been found effective.^4-6 Dietary supplements, such as coenzyme Q10 and l-carnitine, also have not been found effective in placebo-controlled trials.^7,8

The double-blind RCT reported on here looked at whether American ginseng might be effective in relieving cancer-related fatigue.

STUDY SUMMARY

Ginseng reduced fatigue after eight weeks

There are two major species of ginseng—Asian and American—and they have varying amounts, strengths, and varieties of ginsenosides, which are the active ingredients. In this eight-week, double-blind RCT, Barton et al¹ randomly assigned more than 300 patients from 40 US cancer facilities to receive either 1,000 mg of American ginseng twice daily (in the morning and at noon) or matched placebo capsules.

Patients were either currently receiving treatment for cancer or were posttreatment but within two years of receiving a cancer diagnosis. All participants had experienced fatigue of at least a month’s duration that they rated as 4 or higher on a scale of 0 to 10. Patients with other causes of fatigue were excluded, as were those who had pain or insomnia rated 4 or higher, those with brain cancer or central nervous system (CNS) lymphoma, those taking systemic steroids or opioids, and those who were using, or had used, ginseng or other agents for fatigue.

Of the 364 randomized participants, 300 (147 ginseng patients, 153 placebo patients) remained in the study through the primary endpoint at four weeks, and 261 completed the entire eight-week study. There were no baseline differences between groups in demographic characteristics, time since cancer diagnosis, cancer type, current or prior treatment, and fatigue at baseline.

The primary outcome was a change in score on the Multidimensional Fatigue Symptom Inventory–Short Form (MFSI–SF) at four weeks. Secondary outcomes included a change in MFSI–SF score at eight weeks. The authors also conducted a subset analysis comparing ginseng and placebo in only those patients currently undergoing cancer treatment versus those who had completed treatment. To make it easier to compare results, all scores were converted to a 100-point scale; higher scores indicated less fatigue. Adverse events were documented by patient self-report questionnaires and also by researchers who called or visited patients every other week.

While ginseng did not appear to significantly impact fatigue scores versus placebo at four weeks (14.4 vs 8.2), fatigue scores at eight weeks were significantly improved (20 vs 10.3). Interestingly, though, there was a significant improvement in fatigue scores with ginseng at both four weeks and eight weeks when researchers looked at only those patients who were currently receiving cancer treatment. On the other hand, those patients who were not currently undergoing treatment did not show a significant improvement at either time cutoff.

There was no statistically significant difference in adverse events between the ginseng and placebo groups over the eight-week study.

On the next page: What's new >>

WHAT’S NEW

First evidence-based therapy

We now have good evidence that American ginseng (1,000 mg bid) is safe and effective for ameliorating cancer-related fatigue. Before this study, no other effective treatment had been identified.

CAVEATS

Ginseng may not help posttreatment

In this study, ginseng did not improve fatigue at four weeks, which was the primary outcome, although benefits were noted after eight weeks of treatment. Interestingly, though, participants who were receiving radiation and/or chemotherapy during the study experienced significant improvements at four and eight weeks, while those with previous (but not current) treatment did not significantly improve at either time point.

It may be that ginseng works best to ameliorate cancer-related fatigue in patients simultaneously receiving cancer treatment but not in those who have completed treatment. The findings also suggest that patients who have completed treatment may wish to try ginseng for longer than eight weeks to see if it offers any benefit.

Because this study excluded patients with brain cancer, CNS lymphoma, moderate to severe pain, or insomnia and those taking steroids, it is not known if ginseng would help them.

In one study, a low-dose methanolic extract of American ginseng caused a breast cancer cell line to proliferate; however, it was later discovered that this extract had been contaminated with Fusarium fungi containing zearalenone, which has strong estrogenic activity.^9,10 However, higher doses of a similar methanolic extract, as well as other water-based extracts, have reduced proliferation of breast cancer cells.¹¹

Proceed carefully if a patient is taking warfarin. Coadministration of ginseng and warfarin may reduce both warfarin concentrations and a patient’s international normalized ratio (INR).¹² Therefore, carefully monitor INR in patients concurrently taking ginseng and warfarin. Furthermore, ginseng may lower blood glucose in patients with diabetes, so carefully monitor blood glucose in these patients when initiating or discontinuing ginseng.¹³

CHALLENGES TO IMPLEMENTATION

It’s hard to know exactly what you’re getting

Regulating dietary supplements, especially verifying ingredients and potency, has been a challenge for the FDA. Although ginseng commonly is adulterated, this is more common with the Asian species (Panax ginseng) than with the American species (Panax quinquefolius) used in this study.¹⁰ Clinicians who want to recommend ginseng for cancer-related fatigue should advise patients to use American ginseng root products produced in the US. Additionally, the products should contain at least 3% ginsenosides to match the dose used in this study.          

REFERENCES

1. Barton DL, Liu H, Dakhil SR, et al. Wisconsin Ginseng (Panax quinquefolius) to improve cancer-related fatigue: a randomized, double-blind trial, N07C2. J Natl Cancer Inst. 2013;105(16):1230-1238.

2. Hofman M, Ryan JL, Figueroa-Moseley CD, et al. Cancer-related fatigue: the scale of the problem. Oncologist. 2007;12 (suppl 1):4-10.

3. Bower JE, Ganz PA, Desmond KA, et al. Fatigue in long-term breast carcinoma survivors: a longitudinal investigation. Cancer. 2006;106(4):751-758.

4. Moraska AR, Sood A, Dakhil SR, et al. Phase III, randomized, double-blind, placebo-controlled study of long-acting methylphenidate for cancer-related fatigue: North Central Cancer Treatment Group NCCTG-N05C7 trial. J Clin Oncol. 2010;28(23):3673-3679.

5. Bruera E, El Osta B, Valero V, et al. Donepezil for cancer fatigue: a double-blind, randomized, placebo-controlled trial. J Clin Oncol. 2007;25(23):3475-3481.

6. Morrow GR, Hickok JT, Roscoe JA, et al; University of Rochester Cancer Center Community Clinical Oncology Program. Differential effects of paroxetine on fatigue and depression: a randomized, double-blind trial from the University of Rochester Cancer Center Community Clinical Oncology Program. J Clin Oncol. 2003;21(24):4635-4641.

7. Lesser GJ, Case D, Stark N, et al; Wake Forest University Community Clinical Oncology ­Program Research Base. A randomized, double-blind, placebo-controlled study of oral coenzyme Q10 to relieve self-reported treatment-related fatigue in newly diagnosed patients with breast cancer. J Support Oncol. 2013;11(1):31-42.

8. Cruciani RA, Zhang JJ, Manola J, et al. L-carnitine supplementation for the management of fatigue in patients with cancer: an Eastern cooperative oncology group phase III, randomized, double-blind, placebo-controlled trial. J Clin Oncol. 2012;30(31):3864-3869.

9. Duda RB, Zhong Y, Navas V, et al. American ginseng and breast cancer therapeutic agents synergistically inhibit MCF-7
breast cancer cell growth. J Surg Oncol. 1999;72(4):230-239.

10. Upton R, ed. American ginseng root Panax quinquefolius, standards of analysis, quality control, and therapeutics. Scotts Valley, CA: American Herbal Pharmacopoeia; 2012.

11. King ML, Adler SR, Murphy LL. Extraction-dependent effects of American ginseng (Panax quinquefolium) on human breast ­cancer cell proliferation and estrogen receptor activation. Integr Cancer Ther. 2006;5(3): 236-243.

12. Yuan CS, Wei G, Dey L, et al. Brief communication: American ginseng reduces warfarin’s effect in healthy patients: a randomized, controlled trial. Ann Intern Med. 2004;141(1):23-27.

13. Vuksan V, Stavro MP, Sievenpiper JL, et al. Similar postprandial glycemic reductions with escalation of dose and administration time of American ginseng in type 2 diabetes. Diabetes Care. 2000;23(9):1221-1226.

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(5):270-272.

PRACTICE CHANGER

Recommend American ginseng (1,000 mg bid) for four weeks to improve cancer-related fatigue in patients who are undergoing radiation or chemotherapy; no other treatment has been shown to be effective.¹

STRENGTH OF RECOMMENDATION

B: Based on a single well-done randomized controlled trial (RCT).¹

ILLUSTRATIVE CASE

A 54-year-old woman is receiving chemotherapy for adenocarcinoma of the right breast (T2N1M0) and has persistent, disabling fatigue. She has been unable to work or care for her family since starting chemotherapy. She says she gets enough sleep and denies being depressed or in pain. Lab testing for anemia and thyroid dysfunction is negative. Is there a safe and effective intervention?

On the next page: Study summary >>

Cancer-related fatigue is a common, distressing symptom that occurs in more than half of all patients undergoing chemotherapy and more than two-thirds of those receiving radiation therapy.² For many cancer survivors, fatigue can persist for five to 10 years after treatment.³

Because no treatments have proven effective, many clinicians and patients accept fatigue as inevitable. In RCTs, psychostimulants (eg, methylphenidate) and antidepressants (eg, donepezil and paroxetine) have not been found effective.^4-6 Dietary supplements, such as coenzyme Q10 and l-carnitine, also have not been found effective in placebo-controlled trials.^7,8

The double-blind RCT reported on here looked at whether American ginseng might be effective in relieving cancer-related fatigue.

STUDY SUMMARY

Ginseng reduced fatigue after eight weeks

There are two major species of ginseng—Asian and American—and they have varying amounts, strengths, and varieties of ginsenosides, which are the active ingredients. In this eight-week, double-blind RCT, Barton et al¹ randomly assigned more than 300 patients from 40 US cancer facilities to receive either 1,000 mg of American ginseng twice daily (in the morning and at noon) or matched placebo capsules.

Patients were either currently receiving treatment for cancer or were posttreatment but within two years of receiving a cancer diagnosis. All participants had experienced fatigue of at least a month’s duration that they rated as 4 or higher on a scale of 0 to 10. Patients with other causes of fatigue were excluded, as were those who had pain or insomnia rated 4 or higher, those with brain cancer or central nervous system (CNS) lymphoma, those taking systemic steroids or opioids, and those who were using, or had used, ginseng or other agents for fatigue.

Of the 364 randomized participants, 300 (147 ginseng patients, 153 placebo patients) remained in the study through the primary endpoint at four weeks, and 261 completed the entire eight-week study. There were no baseline differences between groups in demographic characteristics, time since cancer diagnosis, cancer type, current or prior treatment, and fatigue at baseline.

The primary outcome was a change in score on the Multidimensional Fatigue Symptom Inventory–Short Form (MFSI–SF) at four weeks. Secondary outcomes included a change in MFSI–SF score at eight weeks. The authors also conducted a subset analysis comparing ginseng and placebo in only those patients currently undergoing cancer treatment versus those who had completed treatment. To make it easier to compare results, all scores were converted to a 100-point scale; higher scores indicated less fatigue. Adverse events were documented by patient self-report questionnaires and also by researchers who called or visited patients every other week.

While ginseng did not appear to significantly impact fatigue scores versus placebo at four weeks (14.4 vs 8.2), fatigue scores at eight weeks were significantly improved (20 vs 10.3). Interestingly, though, there was a significant improvement in fatigue scores with ginseng at both four weeks and eight weeks when researchers looked at only those patients who were currently receiving cancer treatment. On the other hand, those patients who were not currently undergoing treatment did not show a significant improvement at either time cutoff.

There was no statistically significant difference in adverse events between the ginseng and placebo groups over the eight-week study.

On the next page: What's new >>

WHAT’S NEW

First evidence-based therapy

We now have good evidence that American ginseng (1,000 mg bid) is safe and effective for ameliorating cancer-related fatigue. Before this study, no other effective treatment had been identified.

CAVEATS

Ginseng may not help posttreatment

In this study, ginseng did not improve fatigue at four weeks, which was the primary outcome, although benefits were noted after eight weeks of treatment. Interestingly, though, participants who were receiving radiation and/or chemotherapy during the study experienced significant improvements at four and eight weeks, while those with previous (but not current) treatment did not significantly improve at either time point.

It may be that ginseng works best to ameliorate cancer-related fatigue in patients simultaneously receiving cancer treatment but not in those who have completed treatment. The findings also suggest that patients who have completed treatment may wish to try ginseng for longer than eight weeks to see if it offers any benefit.

Because this study excluded patients with brain cancer, CNS lymphoma, moderate to severe pain, or insomnia and those taking steroids, it is not known if ginseng would help them.

In one study, a low-dose methanolic extract of American ginseng caused a breast cancer cell line to proliferate; however, it was later discovered that this extract had been contaminated with Fusarium fungi containing zearalenone, which has strong estrogenic activity.^9,10 However, higher doses of a similar methanolic extract, as well as other water-based extracts, have reduced proliferation of breast cancer cells.¹¹

Proceed carefully if a patient is taking warfarin. Coadministration of ginseng and warfarin may reduce both warfarin concentrations and a patient’s international normalized ratio (INR).¹² Therefore, carefully monitor INR in patients concurrently taking ginseng and warfarin. Furthermore, ginseng may lower blood glucose in patients with diabetes, so carefully monitor blood glucose in these patients when initiating or discontinuing ginseng.¹³

CHALLENGES TO IMPLEMENTATION

It’s hard to know exactly what you’re getting

Regulating dietary supplements, especially verifying ingredients and potency, has been a challenge for the FDA. Although ginseng commonly is adulterated, this is more common with the Asian species (Panax ginseng) than with the American species (Panax quinquefolius) used in this study.¹⁰ Clinicians who want to recommend ginseng for cancer-related fatigue should advise patients to use American ginseng root products produced in the US. Additionally, the products should contain at least 3% ginsenosides to match the dose used in this study.          

REFERENCES

1. Barton DL, Liu H, Dakhil SR, et al. Wisconsin Ginseng (Panax quinquefolius) to improve cancer-related fatigue: a randomized, double-blind trial, N07C2. J Natl Cancer Inst. 2013;105(16):1230-1238.

2. Hofman M, Ryan JL, Figueroa-Moseley CD, et al. Cancer-related fatigue: the scale of the problem. Oncologist. 2007;12 (suppl 1):4-10.

3. Bower JE, Ganz PA, Desmond KA, et al. Fatigue in long-term breast carcinoma survivors: a longitudinal investigation. Cancer. 2006;106(4):751-758.

4. Moraska AR, Sood A, Dakhil SR, et al. Phase III, randomized, double-blind, placebo-controlled study of long-acting methylphenidate for cancer-related fatigue: North Central Cancer Treatment Group NCCTG-N05C7 trial. J Clin Oncol. 2010;28(23):3673-3679.

5. Bruera E, El Osta B, Valero V, et al. Donepezil for cancer fatigue: a double-blind, randomized, placebo-controlled trial. J Clin Oncol. 2007;25(23):3475-3481.

6. Morrow GR, Hickok JT, Roscoe JA, et al; University of Rochester Cancer Center Community Clinical Oncology Program. Differential effects of paroxetine on fatigue and depression: a randomized, double-blind trial from the University of Rochester Cancer Center Community Clinical Oncology Program. J Clin Oncol. 2003;21(24):4635-4641.

7. Lesser GJ, Case D, Stark N, et al; Wake Forest University Community Clinical Oncology ­Program Research Base. A randomized, double-blind, placebo-controlled study of oral coenzyme Q10 to relieve self-reported treatment-related fatigue in newly diagnosed patients with breast cancer. J Support Oncol. 2013;11(1):31-42.

8. Cruciani RA, Zhang JJ, Manola J, et al. L-carnitine supplementation for the management of fatigue in patients with cancer: an Eastern cooperative oncology group phase III, randomized, double-blind, placebo-controlled trial. J Clin Oncol. 2012;30(31):3864-3869.

9. Duda RB, Zhong Y, Navas V, et al. American ginseng and breast cancer therapeutic agents synergistically inhibit MCF-7
breast cancer cell growth. J Surg Oncol. 1999;72(4):230-239.

10. Upton R, ed. American ginseng root Panax quinquefolius, standards of analysis, quality control, and therapeutics. Scotts Valley, CA: American Herbal Pharmacopoeia; 2012.

11. King ML, Adler SR, Murphy LL. Extraction-dependent effects of American ginseng (Panax quinquefolium) on human breast ­cancer cell proliferation and estrogen receptor activation. Integr Cancer Ther. 2006;5(3): 236-243.

12. Yuan CS, Wei G, Dey L, et al. Brief communication: American ginseng reduces warfarin’s effect in healthy patients: a randomized, controlled trial. Ann Intern Med. 2004;141(1):23-27.

13. Vuksan V, Stavro MP, Sievenpiper JL, et al. Similar postprandial glycemic reductions with escalation of dose and administration time of American ginseng in type 2 diabetes. Diabetes Care. 2000;23(9):1221-1226.

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(5):270-272.

PRACTICE CHANGER

Recommend American ginseng (1,000 mg bid) for four weeks to improve cancer-related fatigue in patients who are undergoing radiation or chemotherapy; no other treatment has been shown to be effective.¹

STRENGTH OF RECOMMENDATION

B: Based on a single well-done randomized controlled trial (RCT).¹

ILLUSTRATIVE CASE

A 54-year-old woman is receiving chemotherapy for adenocarcinoma of the right breast (T2N1M0) and has persistent, disabling fatigue. She has been unable to work or care for her family since starting chemotherapy. She says she gets enough sleep and denies being depressed or in pain. Lab testing for anemia and thyroid dysfunction is negative. Is there a safe and effective intervention?

On the next page: Study summary >>

Cancer-related fatigue is a common, distressing symptom that occurs in more than half of all patients undergoing chemotherapy and more than two-thirds of those receiving radiation therapy.² For many cancer survivors, fatigue can persist for five to 10 years after treatment.³

Because no treatments have proven effective, many clinicians and patients accept fatigue as inevitable. In RCTs, psychostimulants (eg, methylphenidate) and antidepressants (eg, donepezil and paroxetine) have not been found effective.^4-6 Dietary supplements, such as coenzyme Q10 and l-carnitine, also have not been found effective in placebo-controlled trials.^7,8

The double-blind RCT reported on here looked at whether American ginseng might be effective in relieving cancer-related fatigue.

STUDY SUMMARY

Ginseng reduced fatigue after eight weeks

There are two major species of ginseng—Asian and American—and they have varying amounts, strengths, and varieties of ginsenosides, which are the active ingredients. In this eight-week, double-blind RCT, Barton et al¹ randomly assigned more than 300 patients from 40 US cancer facilities to receive either 1,000 mg of American ginseng twice daily (in the morning and at noon) or matched placebo capsules.

Patients were either currently receiving treatment for cancer or were posttreatment but within two years of receiving a cancer diagnosis. All participants had experienced fatigue of at least a month’s duration that they rated as 4 or higher on a scale of 0 to 10. Patients with other causes of fatigue were excluded, as were those who had pain or insomnia rated 4 or higher, those with brain cancer or central nervous system (CNS) lymphoma, those taking systemic steroids or opioids, and those who were using, or had used, ginseng or other agents for fatigue.

Of the 364 randomized participants, 300 (147 ginseng patients, 153 placebo patients) remained in the study through the primary endpoint at four weeks, and 261 completed the entire eight-week study. There were no baseline differences between groups in demographic characteristics, time since cancer diagnosis, cancer type, current or prior treatment, and fatigue at baseline.

The primary outcome was a change in score on the Multidimensional Fatigue Symptom Inventory–Short Form (MFSI–SF) at four weeks. Secondary outcomes included a change in MFSI–SF score at eight weeks. The authors also conducted a subset analysis comparing ginseng and placebo in only those patients currently undergoing cancer treatment versus those who had completed treatment. To make it easier to compare results, all scores were converted to a 100-point scale; higher scores indicated less fatigue. Adverse events were documented by patient self-report questionnaires and also by researchers who called or visited patients every other week.

While ginseng did not appear to significantly impact fatigue scores versus placebo at four weeks (14.4 vs 8.2), fatigue scores at eight weeks were significantly improved (20 vs 10.3). Interestingly, though, there was a significant improvement in fatigue scores with ginseng at both four weeks and eight weeks when researchers looked at only those patients who were currently receiving cancer treatment. On the other hand, those patients who were not currently undergoing treatment did not show a significant improvement at either time cutoff.

There was no statistically significant difference in adverse events between the ginseng and placebo groups over the eight-week study.

On the next page: What's new >>

WHAT’S NEW

First evidence-based therapy

We now have good evidence that American ginseng (1,000 mg bid) is safe and effective for ameliorating cancer-related fatigue. Before this study, no other effective treatment had been identified.

CAVEATS

Ginseng may not help posttreatment

In this study, ginseng did not improve fatigue at four weeks, which was the primary outcome, although benefits were noted after eight weeks of treatment. Interestingly, though, participants who were receiving radiation and/or chemotherapy during the study experienced significant improvements at four and eight weeks, while those with previous (but not current) treatment did not significantly improve at either time point.

It may be that ginseng works best to ameliorate cancer-related fatigue in patients simultaneously receiving cancer treatment but not in those who have completed treatment. The findings also suggest that patients who have completed treatment may wish to try ginseng for longer than eight weeks to see if it offers any benefit.

Because this study excluded patients with brain cancer, CNS lymphoma, moderate to severe pain, or insomnia and those taking steroids, it is not known if ginseng would help them.

In one study, a low-dose methanolic extract of American ginseng caused a breast cancer cell line to proliferate; however, it was later discovered that this extract had been contaminated with Fusarium fungi containing zearalenone, which has strong estrogenic activity.^9,10 However, higher doses of a similar methanolic extract, as well as other water-based extracts, have reduced proliferation of breast cancer cells.¹¹

Proceed carefully if a patient is taking warfarin. Coadministration of ginseng and warfarin may reduce both warfarin concentrations and a patient’s international normalized ratio (INR).¹² Therefore, carefully monitor INR in patients concurrently taking ginseng and warfarin. Furthermore, ginseng may lower blood glucose in patients with diabetes, so carefully monitor blood glucose in these patients when initiating or discontinuing ginseng.¹³

CHALLENGES TO IMPLEMENTATION

It’s hard to know exactly what you’re getting

Regulating dietary supplements, especially verifying ingredients and potency, has been a challenge for the FDA. Although ginseng commonly is adulterated, this is more common with the Asian species (Panax ginseng) than with the American species (Panax quinquefolius) used in this study.¹⁰ Clinicians who want to recommend ginseng for cancer-related fatigue should advise patients to use American ginseng root products produced in the US. Additionally, the products should contain at least 3% ginsenosides to match the dose used in this study.          

REFERENCES

1. Barton DL, Liu H, Dakhil SR, et al. Wisconsin Ginseng (Panax quinquefolius) to improve cancer-related fatigue: a randomized, double-blind trial, N07C2. J Natl Cancer Inst. 2013;105(16):1230-1238.

2. Hofman M, Ryan JL, Figueroa-Moseley CD, et al. Cancer-related fatigue: the scale of the problem. Oncologist. 2007;12 (suppl 1):4-10.

3. Bower JE, Ganz PA, Desmond KA, et al. Fatigue in long-term breast carcinoma survivors: a longitudinal investigation. Cancer. 2006;106(4):751-758.

4. Moraska AR, Sood A, Dakhil SR, et al. Phase III, randomized, double-blind, placebo-controlled study of long-acting methylphenidate for cancer-related fatigue: North Central Cancer Treatment Group NCCTG-N05C7 trial. J Clin Oncol. 2010;28(23):3673-3679.

5. Bruera E, El Osta B, Valero V, et al. Donepezil for cancer fatigue: a double-blind, randomized, placebo-controlled trial. J Clin Oncol. 2007;25(23):3475-3481.

6. Morrow GR, Hickok JT, Roscoe JA, et al; University of Rochester Cancer Center Community Clinical Oncology Program. Differential effects of paroxetine on fatigue and depression: a randomized, double-blind trial from the University of Rochester Cancer Center Community Clinical Oncology Program. J Clin Oncol. 2003;21(24):4635-4641.

7. Lesser GJ, Case D, Stark N, et al; Wake Forest University Community Clinical Oncology ­Program Research Base. A randomized, double-blind, placebo-controlled study of oral coenzyme Q10 to relieve self-reported treatment-related fatigue in newly diagnosed patients with breast cancer. J Support Oncol. 2013;11(1):31-42.

8. Cruciani RA, Zhang JJ, Manola J, et al. L-carnitine supplementation for the management of fatigue in patients with cancer: an Eastern cooperative oncology group phase III, randomized, double-blind, placebo-controlled trial. J Clin Oncol. 2012;30(31):3864-3869.

9. Duda RB, Zhong Y, Navas V, et al. American ginseng and breast cancer therapeutic agents synergistically inhibit MCF-7
breast cancer cell growth. J Surg Oncol. 1999;72(4):230-239.

10. Upton R, ed. American ginseng root Panax quinquefolius, standards of analysis, quality control, and therapeutics. Scotts Valley, CA: American Herbal Pharmacopoeia; 2012.

11. King ML, Adler SR, Murphy LL. Extraction-dependent effects of American ginseng (Panax quinquefolium) on human breast ­cancer cell proliferation and estrogen receptor activation. Integr Cancer Ther. 2006;5(3): 236-243.

12. Yuan CS, Wei G, Dey L, et al. Brief communication: American ginseng reduces warfarin’s effect in healthy patients: a randomized, controlled trial. Ann Intern Med. 2004;141(1):23-27.

13. Vuksan V, Stavro MP, Sievenpiper JL, et al. Similar postprandial glycemic reductions with escalation of dose and administration time of American ginseng in type 2 diabetes. Diabetes Care. 2000;23(9):1221-1226.

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(5):270-272.

Illustrative case

A 54-year-old woman is receiving chemotherapy for adenocarcinoma of the right breast (T2N1M0) and has persistent, disabling fatigue. She has been unable to work or care for her family since starting chemotherapy. She says she gets enough sleep and denies being depressed or in pain. Lab testing for anemia and thyroid dysfunction is negative.

Is there a safe and effective intervention that can reduce her fatigue?

Cancer-related fatigue is a common, distressing symptom that occurs in more than half of all patients undergoing chemotherapy and over two-thirds of those receiving radiation therapy.² For many cancer survivors, fatigue can persist for 5 to 10 years after treatment._³ Because no treatments have been effective, many clinicians and patients accept it as inevitable. In RCTs, psychostimulants such as methylphenidate and antidepressants such as donepezil and paroxetine have not been found effective.^4-6 Dietary supplements such as coenzyme Q10 and L-Carnitine also have not been found effective in placebo-controlled trials.^7,8 The double-blind RCT reported on here looked at whether American ginseng might be effective in relieving cancer-related fatigue.

STUDY SUMMARY: Ginseng reduced fatigue after 8 weeks of treatment

There are 2 major species of ginseng—Asian and American—and they have varying amounts, strengths, and varieties of ginsenosides, which are the active ingredients. In this 8-week, double-blind RCT, Barton et al¹ randomized more than 300 patients from 40 US cancer facilities to receive either 1000 mg of American ginseng twice daily (in the morning and at noon) or matched placebo capsules. Patients were either currently receiving treatment for cancer or were posttreatment, but within 2 years of receiving a cancer diagnosis. All participants had experienced fatigue for at least a month that they rated as ≥4 or higher on a scale of 0 to 10. Patients with other causes of fatigue were excluded, as were those who had pain or insomnia rated ≥4 on a scale of 0 to 10, those with brain cancer or central nervous system (CNS) lymphoma, those taking systemic steroids or opioids, and those who were using, or had used, ginseng or other agents for fatigue.

Of the 364 randomized participants, 300 (147 ginseng patients, 153 placebo patients) remained in the study through the primary endpoint at 4 weeks, and 261 completed the entire 8-week study. There were no baseline differences between groups in demographic characteristics, time since cancer diagnosis, cancer type, current or prior treatment, and fatigue at baseline.

The primary outcome was a change in score on the Multidimensional Fatigue Symptom Inventory–Short Form (MFSI-SF) at 4 weeks. Secondary outcomes included a change in MFSI-SF score at 8 weeks. The authors also conducted a subset analysis comparing ginseng vs placebo in just those patients currently undergoing cancer treatment vs those who had completed treatment. To make it easier to compare results, all scores were converted to a 100-point scale; higher scores indicated less fatigue. Adverse events were documented by patient self-report questionnaires and also by researchers who called or visited patients every other week.

While ginseng did not appear to significantly increase the change in fatigue scores over placebo at 4 weeks (14.4 vs 8.2; P=.07), fatigue scores at 8 weeks were significantly improved (20 vs 10.3; P=.003). Interestingly, though, there was a significant improvement in fatigue scores with ginseng at both 4 weeks (P=.02) and 8 weeks (P=.01) when researchers looked at only those patients who were currently receiving cancer treatment. On the other hand, those patients who were not currently undergoing treatment did not show a significant improvement at either time cutoff.

There was no statistically significant difference in adverse events between the ginseng and placebo groups over the 8-week study.

WHAT'S NEW: The first evidence-based therapy for cancer-related fatigue

We now have good evidence that American ginseng 1000 mg twice daily is safe and effective for ameliorating cancer-related fatigue. Before this study, no other effective treatments had been identified.

CAVEATS: Ginseng may not help patients who've finished cancer treatment

In this study, ginseng did not improve fatigue at 4 weeks, which was the primary outcome, although benefits were noted after 8 weeks of treatment. Interestingly, though, participants who were receiving radiation and/or chemotherapy during the study experienced significant improvements at 4 and 8 weeks, while those with previous (but not current) treatment did not significantly improve at either time point.

Coadministration of ginseng and warfarin may reduce both warfarin concentrations and a patient's INR.It may be that ginseng works best to ameliorate cancer-related fatigue in patients simultaneously receiving cancer treatment, but not in those who have completed treatment. The findings also suggest that patients who have completed treatment may wish to try ginseng for longer than 8 weeks to see if it offers any benefit.

Because this study excluded patients with brain cancer, CNS lymphoma, moderate to severe pain, or insomnia and those taking steroids, it is not known if ginseng would help them.

In one study, a low-dose methanolic extract of American ginseng caused a breast cancer cell line to proliferate; however, it was later discovered that this extract had been contaminated with Fusarium fungi containing zearalenone, which has strong estrogenic activity.^9,10 However, higher doses of a similar methanolic extract, as well as other water-based extracts, have reduced proliferation of breast cancer cells.¹¹

Proceed carefully if a patient is taking warfarin. Coadministration of ginseng and warfarin may reduce both warfarin concentrations and a patient’s international normalized ratio (INR).¹² Therefore, carefully monitor INR in patients concurrently taking ginseng and warfarin. Furthermore, ginseng may lower blood glucose in patients with diabetes, so carefully monitor blood glucose in these patients when initiating or discontinuing ginseng.¹³

CHALLENGES TO IMPLEMENTATION: With ginseng, it's hard to know exactly what you're getting

Advise patients to obtain American ginseng products that contain at least 3% ginsenosides.Regulating dietary supplements has been a challenge for the US Food and Drug Administration, especially verifying ingredients and potency. Although ginseng commonly is adulterated, much of the adulteration occurs with the Asian species (Panax ginseng) rather than the American species (Panax quinquefolius) used in this study.¹⁰ Physicians who want to recommend ginseng for cancer-related fatigue should advise patients to use American ginseng root products produced in the United States. Additionally, ginseng products should contain at least 3% ginsenosides to match the dose used in this study.

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 54-year-old woman is receiving chemotherapy for adenocarcinoma of the right breast (T2N1M0) and has persistent, disabling fatigue. She has been unable to work or care for her family since starting chemotherapy. She says she gets enough sleep and denies being depressed or in pain. Lab testing for anemia and thyroid dysfunction is negative.

Is there a safe and effective intervention that can reduce her fatigue?

Cancer-related fatigue is a common, distressing symptom that occurs in more than half of all patients undergoing chemotherapy and over two-thirds of those receiving radiation therapy.² For many cancer survivors, fatigue can persist for 5 to 10 years after treatment._³ Because no treatments have been effective, many clinicians and patients accept it as inevitable. In RCTs, psychostimulants such as methylphenidate and antidepressants such as donepezil and paroxetine have not been found effective.^4-6 Dietary supplements such as coenzyme Q10 and L-Carnitine also have not been found effective in placebo-controlled trials.^7,8 The double-blind RCT reported on here looked at whether American ginseng might be effective in relieving cancer-related fatigue.

STUDY SUMMARY: Ginseng reduced fatigue after 8 weeks of treatment

There are 2 major species of ginseng—Asian and American—and they have varying amounts, strengths, and varieties of ginsenosides, which are the active ingredients. In this 8-week, double-blind RCT, Barton et al¹ randomized more than 300 patients from 40 US cancer facilities to receive either 1000 mg of American ginseng twice daily (in the morning and at noon) or matched placebo capsules. Patients were either currently receiving treatment for cancer or were posttreatment, but within 2 years of receiving a cancer diagnosis. All participants had experienced fatigue for at least a month that they rated as ≥4 or higher on a scale of 0 to 10. Patients with other causes of fatigue were excluded, as were those who had pain or insomnia rated ≥4 on a scale of 0 to 10, those with brain cancer or central nervous system (CNS) lymphoma, those taking systemic steroids or opioids, and those who were using, or had used, ginseng or other agents for fatigue.

Of the 364 randomized participants, 300 (147 ginseng patients, 153 placebo patients) remained in the study through the primary endpoint at 4 weeks, and 261 completed the entire 8-week study. There were no baseline differences between groups in demographic characteristics, time since cancer diagnosis, cancer type, current or prior treatment, and fatigue at baseline.

The primary outcome was a change in score on the Multidimensional Fatigue Symptom Inventory–Short Form (MFSI-SF) at 4 weeks. Secondary outcomes included a change in MFSI-SF score at 8 weeks. The authors also conducted a subset analysis comparing ginseng vs placebo in just those patients currently undergoing cancer treatment vs those who had completed treatment. To make it easier to compare results, all scores were converted to a 100-point scale; higher scores indicated less fatigue. Adverse events were documented by patient self-report questionnaires and also by researchers who called or visited patients every other week.

While ginseng did not appear to significantly increase the change in fatigue scores over placebo at 4 weeks (14.4 vs 8.2; P=.07), fatigue scores at 8 weeks were significantly improved (20 vs 10.3; P=.003). Interestingly, though, there was a significant improvement in fatigue scores with ginseng at both 4 weeks (P=.02) and 8 weeks (P=.01) when researchers looked at only those patients who were currently receiving cancer treatment. On the other hand, those patients who were not currently undergoing treatment did not show a significant improvement at either time cutoff.

There was no statistically significant difference in adverse events between the ginseng and placebo groups over the 8-week study.

WHAT'S NEW: The first evidence-based therapy for cancer-related fatigue

We now have good evidence that American ginseng 1000 mg twice daily is safe and effective for ameliorating cancer-related fatigue. Before this study, no other effective treatments had been identified.

CAVEATS: Ginseng may not help patients who've finished cancer treatment

In this study, ginseng did not improve fatigue at 4 weeks, which was the primary outcome, although benefits were noted after 8 weeks of treatment. Interestingly, though, participants who were receiving radiation and/or chemotherapy during the study experienced significant improvements at 4 and 8 weeks, while those with previous (but not current) treatment did not significantly improve at either time point.

Coadministration of ginseng and warfarin may reduce both warfarin concentrations and a patient's INR.It may be that ginseng works best to ameliorate cancer-related fatigue in patients simultaneously receiving cancer treatment, but not in those who have completed treatment. The findings also suggest that patients who have completed treatment may wish to try ginseng for longer than 8 weeks to see if it offers any benefit.

Because this study excluded patients with brain cancer, CNS lymphoma, moderate to severe pain, or insomnia and those taking steroids, it is not known if ginseng would help them.

In one study, a low-dose methanolic extract of American ginseng caused a breast cancer cell line to proliferate; however, it was later discovered that this extract had been contaminated with Fusarium fungi containing zearalenone, which has strong estrogenic activity.^9,10 However, higher doses of a similar methanolic extract, as well as other water-based extracts, have reduced proliferation of breast cancer cells.¹¹

Proceed carefully if a patient is taking warfarin. Coadministration of ginseng and warfarin may reduce both warfarin concentrations and a patient’s international normalized ratio (INR).¹² Therefore, carefully monitor INR in patients concurrently taking ginseng and warfarin. Furthermore, ginseng may lower blood glucose in patients with diabetes, so carefully monitor blood glucose in these patients when initiating or discontinuing ginseng.¹³

CHALLENGES TO IMPLEMENTATION: With ginseng, it's hard to know exactly what you're getting

Advise patients to obtain American ginseng products that contain at least 3% ginsenosides.Regulating dietary supplements has been a challenge for the US Food and Drug Administration, especially verifying ingredients and potency. Although ginseng commonly is adulterated, much of the adulteration occurs with the Asian species (Panax ginseng) rather than the American species (Panax quinquefolius) used in this study.¹⁰ Physicians who want to recommend ginseng for cancer-related fatigue should advise patients to use American ginseng root products produced in the United States. Additionally, ginseng products should contain at least 3% ginsenosides to match the dose used in this study.

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 54-year-old woman is receiving chemotherapy for adenocarcinoma of the right breast (T2N1M0) and has persistent, disabling fatigue. She has been unable to work or care for her family since starting chemotherapy. She says she gets enough sleep and denies being depressed or in pain. Lab testing for anemia and thyroid dysfunction is negative.

Is there a safe and effective intervention that can reduce her fatigue?

Cancer-related fatigue is a common, distressing symptom that occurs in more than half of all patients undergoing chemotherapy and over two-thirds of those receiving radiation therapy.² For many cancer survivors, fatigue can persist for 5 to 10 years after treatment._³ Because no treatments have been effective, many clinicians and patients accept it as inevitable. In RCTs, psychostimulants such as methylphenidate and antidepressants such as donepezil and paroxetine have not been found effective.^4-6 Dietary supplements such as coenzyme Q10 and L-Carnitine also have not been found effective in placebo-controlled trials.^7,8 The double-blind RCT reported on here looked at whether American ginseng might be effective in relieving cancer-related fatigue.

STUDY SUMMARY: Ginseng reduced fatigue after 8 weeks of treatment

There are 2 major species of ginseng—Asian and American—and they have varying amounts, strengths, and varieties of ginsenosides, which are the active ingredients. In this 8-week, double-blind RCT, Barton et al¹ randomized more than 300 patients from 40 US cancer facilities to receive either 1000 mg of American ginseng twice daily (in the morning and at noon) or matched placebo capsules. Patients were either currently receiving treatment for cancer or were posttreatment, but within 2 years of receiving a cancer diagnosis. All participants had experienced fatigue for at least a month that they rated as ≥4 or higher on a scale of 0 to 10. Patients with other causes of fatigue were excluded, as were those who had pain or insomnia rated ≥4 on a scale of 0 to 10, those with brain cancer or central nervous system (CNS) lymphoma, those taking systemic steroids or opioids, and those who were using, or had used, ginseng or other agents for fatigue.

Of the 364 randomized participants, 300 (147 ginseng patients, 153 placebo patients) remained in the study through the primary endpoint at 4 weeks, and 261 completed the entire 8-week study. There were no baseline differences between groups in demographic characteristics, time since cancer diagnosis, cancer type, current or prior treatment, and fatigue at baseline.

The primary outcome was a change in score on the Multidimensional Fatigue Symptom Inventory–Short Form (MFSI-SF) at 4 weeks. Secondary outcomes included a change in MFSI-SF score at 8 weeks. The authors also conducted a subset analysis comparing ginseng vs placebo in just those patients currently undergoing cancer treatment vs those who had completed treatment. To make it easier to compare results, all scores were converted to a 100-point scale; higher scores indicated less fatigue. Adverse events were documented by patient self-report questionnaires and also by researchers who called or visited patients every other week.

While ginseng did not appear to significantly increase the change in fatigue scores over placebo at 4 weeks (14.4 vs 8.2; P=.07), fatigue scores at 8 weeks were significantly improved (20 vs 10.3; P=.003). Interestingly, though, there was a significant improvement in fatigue scores with ginseng at both 4 weeks (P=.02) and 8 weeks (P=.01) when researchers looked at only those patients who were currently receiving cancer treatment. On the other hand, those patients who were not currently undergoing treatment did not show a significant improvement at either time cutoff.

There was no statistically significant difference in adverse events between the ginseng and placebo groups over the 8-week study.

WHAT'S NEW: The first evidence-based therapy for cancer-related fatigue

We now have good evidence that American ginseng 1000 mg twice daily is safe and effective for ameliorating cancer-related fatigue. Before this study, no other effective treatments had been identified.

CAVEATS: Ginseng may not help patients who've finished cancer treatment

In this study, ginseng did not improve fatigue at 4 weeks, which was the primary outcome, although benefits were noted after 8 weeks of treatment. Interestingly, though, participants who were receiving radiation and/or chemotherapy during the study experienced significant improvements at 4 and 8 weeks, while those with previous (but not current) treatment did not significantly improve at either time point.

Coadministration of ginseng and warfarin may reduce both warfarin concentrations and a patient's INR.It may be that ginseng works best to ameliorate cancer-related fatigue in patients simultaneously receiving cancer treatment, but not in those who have completed treatment. The findings also suggest that patients who have completed treatment may wish to try ginseng for longer than 8 weeks to see if it offers any benefit.

Because this study excluded patients with brain cancer, CNS lymphoma, moderate to severe pain, or insomnia and those taking steroids, it is not known if ginseng would help them.

In one study, a low-dose methanolic extract of American ginseng caused a breast cancer cell line to proliferate; however, it was later discovered that this extract had been contaminated with Fusarium fungi containing zearalenone, which has strong estrogenic activity.^9,10 However, higher doses of a similar methanolic extract, as well as other water-based extracts, have reduced proliferation of breast cancer cells.¹¹

Proceed carefully if a patient is taking warfarin. Coadministration of ginseng and warfarin may reduce both warfarin concentrations and a patient’s international normalized ratio (INR).¹² Therefore, carefully monitor INR in patients concurrently taking ginseng and warfarin. Furthermore, ginseng may lower blood glucose in patients with diabetes, so carefully monitor blood glucose in these patients when initiating or discontinuing ginseng.¹³

CHALLENGES TO IMPLEMENTATION: With ginseng, it's hard to know exactly what you're getting

Advise patients to obtain American ginseng products that contain at least 3% ginsenosides.Regulating dietary supplements has been a challenge for the US Food and Drug Administration, especially verifying ingredients and potency. Although ginseng commonly is adulterated, much of the adulteration occurs with the Asian species (Panax ginseng) rather than the American species (Panax quinquefolius) used in this study.¹⁰ Physicians who want to recommend ginseng for cancer-related fatigue should advise patients to use American ginseng root products produced in the United States. Additionally, ginseng products should contain at least 3% ginsenosides to match the dose used in this study.

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

Prescribe a five-day regimen of glucocorticoid therapy for acute exacerbations of chronic obstructive pulmonary disease (COPD); the shorter course of treatment appears to be as effective as a 14-day regimen.¹

Strength of ­recommendation

B: Based on a single well-­designed randomized controlled trial (RCT).¹

ILLUSTRATIVE CASE

A 55-year-old man with COPD presents to the emergency department (ED) with progressive shortness of breath, cough, and sputum production in the past four days. He is diagnosed with a COPD exacerbation, treated with corticosteroids, and admitted to the hospital. His inpatient treatment includes antibiotics, inhaled albuterol and ipratropium, supplemental oxygen, and oral corticosteroids.

How many days should he take oral steroids?

Severe exacerbations of COPD are independently associated with mortality,² regardless of baseline severity. Guidelines and systematic reviews highlight the importance of using oral glucocorticoids in the management of acute COPD exacerbations, as the drugs have been found to shorten recovery time and length of hospital stay, improve lung function, and reduce the risk for early relapse and treatment failure.^3-5 What is not clear is how long the course of oral steroids should be.

What we know (and don’t know) about duration

Data supporting a 14-day course of steroids versus a longer (eight-week) duration come from the Systemic Corticosteroids in COPD Exacerbations trial.⁶ Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria suggest a 10- to 14-day regimen (30 to 40 mg/d) but acknowledge that there is a lack of data from clinical and observational studies to support this recommendation.³ A recent Cochrane review compared a short course of treatment (three to seven days) with a longer regimen (10 to 15 days) and found that the evidence to support a clinical practice change was inconclusive.⁵

The study detailed in this PURL—a double-blind RCT comparing five-day with 14-day oral steroid treatment in patients ­hospitalized for acute COPD exacerbation—had more definitive results.¹

Continue reading for the study summary...

STUDY SUMMARY

Shorter and longer regimens produce equal results

Leuppi et al¹ used noninferiority methodology to compare a five- and a 14-day course of prednisone 40 mg/d to treat patients with COPD exacerbations. A patient was considered to have an exacerbation if he or she had a change from baseline in two or more of the following: dyspnea, cough, sputum quantity, or purulence.

Participants were patients who presented to the EDs of five Swiss teaching hospitals between March 2006 and February 2011. To be eligible, individuals had to be 40 or older and have at least 20 pack-years of smoking. Exclusion criteria included asthma, mild obstruction (FEV₁/FVC > 70%), pneumonia, an estimated survival of less than six months, pregnancy, and lactation.

All the participants (N = 311) received 40 mg methylprednisolone intravenously on day 1, followed by prednisone 40 mg orally on days 2 through 5. The researchers then randomly divided participants into two groups: One group continued to take prednisone 40 mg/d and the other group received a matching placebo for an additional nine days. Participants in both groups also received antibiotics for seven days, twice-daily inhaled steroids, daily tiotropium, and nebulized albuterol, as needed; additional oral glucocorticoids could be administered, as well, at the discretion of the treating physicians.

The primary outcome was the time to the next COPD exacerbation, up to 180 days. Noninferiority between the groups was defined as no more than a 15% absolute increase in exacerbations. The dropout rate was 5.7%, evenly divided between groups. Intention to treat and per-protocol analyses were conducted, and hazard ratios (HRs) were calculated using the Kaplan-Meier method and Cox proportional hazards models.

The time to next COPD exacerbation did not differ between the study groups: 56 days for those on the five-day steroid regimen versus 57 days for those on the
14-day regimen in the intention-to-treat analysis (HR, 0.95). Sensitivity analyses adjusting for baseline characteristics provided similar results, as did the per-protocol analysis.

Secondary outcomes (overall survival; need for mechanical ventilation; need for additional corticosteroids; and clinical performance measures, such as dyspnea score and quality of life) also did not differ between groups. Nor were there differences in hyperglycemia, worsening hypertension, infection, or other adverse effects typically associated with glucocorticoid use. The active treatment group took more than 400 mg more prednisone than the placebo group (mean, 793 mg vs 379 mg, respectively).

WHAT’S NEW?

Now we know: five days is enough

While randomized trials have found that glucocorticoids improve COPD symptoms, the optimal treatment dose and duration were not known. Indeed, current guidelines recommend treatment for more than five days.³ This trial clearly demonstrated that 40-mg prednisone for five days is at least as good as a 14-day treatment course. Furthermore, it is un­necessary to taper the short-course therapy, which simplifies the regimen.

CAVEATS

Will the results apply to those less severely ill?

More than 80% of patients with acute COPD exacerbations can be managed in an outpatient setting.³ However, participants in this trial were hospitalized for a median of 8.5 days, and most had severe or very severe COPD—and thus, were not fully representative of COPD patients typically seen in an outpatient practice. Yet patients with less severe disease should be at least as likely to ­respond to short-course steroids as those whose COPD is more ­severe.

It is important to note that participants in this study all received optimal guideline-based therapies during hospitalization, which may be difficult to achieve for some patients treated in an outpatient setting. Finally, treatment adherence observed during the hospitalization period in this trial is unlikely to be replicated in the outpatient setting.

CHALLENGES TO IMPLEMENTATION

Identifying patients who need steroids for a longer duration

For patients with new COPD exacerbations or those successfully treated using short-course therapy in the past, a five-day regimen may be appropriate. For those in whom prior attempts at short-course treatment have failed, however, a 14-day course of treatment may be more advisable. That said, no guidelines are available to help us determine which patients previously treated with a longer regimen will find the shorter course of treatment unsuccessful.

Continue for references...

REFERENCES

1. Leuppi JD, Schuetz P, Bingisser R, et al. Short-term vs conventional glucocorticoid therapy in acute exacerbations of chronic obstructive pulmonary disease: the REDUCE randomized clinical trial. JAMA. 2013;309:2223-2231.

2. Soler-Cataluna JJ, Martinez-Garcia MA, Roman Sanchez P, et al. Severe acute exacerbations and mortality in patients with chronic obstructive pulmonary disease. Thorax. 2005;60:925-931.

3. Global Initiative for Chronic Obstructive Lung Disease, Inc. The global strategy for diagnosis, management, and prevention of chronic obstructive pulmonary disease. www.goldcopd.org. Accessed January 9, 2014.

4. Quon BS, Gan WQ, Sin DD. Contemporary management of acute exacerbations of COPD: a systematic review and metaanalysis. Chest. 2008;133:756-766.

5. Walters JA, Wang W, Morley C, et al. Different durations of corticosteroid therapy for exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2011; (10):CD006897.

6. Niewoehner DE, Erbland ML, Deupree RH, et al. Effect of systemic glucocorticoids on exacerbations of chronic obstructive pulmonary disease. Department of Veterans Affairs Cooperative Study Group. N Engl J Med. 1999;340:1941-1947.

ACKNOWLEDGEMENT

The PURLs Surveillance System is supported in part by Grant Number UL 1RR 024999 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(1):29-30, 32.

PRACTICE CHANGER

Prescribe a five-day regimen of glucocorticoid therapy for acute exacerbations of chronic obstructive pulmonary disease (COPD); the shorter course of treatment appears to be as effective as a 14-day regimen.¹

Strength of ­recommendation

B: Based on a single well-­designed randomized controlled trial (RCT).¹

ILLUSTRATIVE CASE

A 55-year-old man with COPD presents to the emergency department (ED) with progressive shortness of breath, cough, and sputum production in the past four days. He is diagnosed with a COPD exacerbation, treated with corticosteroids, and admitted to the hospital. His inpatient treatment includes antibiotics, inhaled albuterol and ipratropium, supplemental oxygen, and oral corticosteroids.

How many days should he take oral steroids?

Severe exacerbations of COPD are independently associated with mortality,² regardless of baseline severity. Guidelines and systematic reviews highlight the importance of using oral glucocorticoids in the management of acute COPD exacerbations, as the drugs have been found to shorten recovery time and length of hospital stay, improve lung function, and reduce the risk for early relapse and treatment failure.^3-5 What is not clear is how long the course of oral steroids should be.

What we know (and don’t know) about duration

Data supporting a 14-day course of steroids versus a longer (eight-week) duration come from the Systemic Corticosteroids in COPD Exacerbations trial.⁶ Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria suggest a 10- to 14-day regimen (30 to 40 mg/d) but acknowledge that there is a lack of data from clinical and observational studies to support this recommendation.³ A recent Cochrane review compared a short course of treatment (three to seven days) with a longer regimen (10 to 15 days) and found that the evidence to support a clinical practice change was inconclusive.⁵

The study detailed in this PURL—a double-blind RCT comparing five-day with 14-day oral steroid treatment in patients ­hospitalized for acute COPD exacerbation—had more definitive results.¹

Continue reading for the study summary...

STUDY SUMMARY

Shorter and longer regimens produce equal results

Leuppi et al¹ used noninferiority methodology to compare a five- and a 14-day course of prednisone 40 mg/d to treat patients with COPD exacerbations. A patient was considered to have an exacerbation if he or she had a change from baseline in two or more of the following: dyspnea, cough, sputum quantity, or purulence.

Participants were patients who presented to the EDs of five Swiss teaching hospitals between March 2006 and February 2011. To be eligible, individuals had to be 40 or older and have at least 20 pack-years of smoking. Exclusion criteria included asthma, mild obstruction (FEV₁/FVC > 70%), pneumonia, an estimated survival of less than six months, pregnancy, and lactation.

All the participants (N = 311) received 40 mg methylprednisolone intravenously on day 1, followed by prednisone 40 mg orally on days 2 through 5. The researchers then randomly divided participants into two groups: One group continued to take prednisone 40 mg/d and the other group received a matching placebo for an additional nine days. Participants in both groups also received antibiotics for seven days, twice-daily inhaled steroids, daily tiotropium, and nebulized albuterol, as needed; additional oral glucocorticoids could be administered, as well, at the discretion of the treating physicians.

The primary outcome was the time to the next COPD exacerbation, up to 180 days. Noninferiority between the groups was defined as no more than a 15% absolute increase in exacerbations. The dropout rate was 5.7%, evenly divided between groups. Intention to treat and per-protocol analyses were conducted, and hazard ratios (HRs) were calculated using the Kaplan-Meier method and Cox proportional hazards models.

The time to next COPD exacerbation did not differ between the study groups: 56 days for those on the five-day steroid regimen versus 57 days for those on the
14-day regimen in the intention-to-treat analysis (HR, 0.95). Sensitivity analyses adjusting for baseline characteristics provided similar results, as did the per-protocol analysis.

Secondary outcomes (overall survival; need for mechanical ventilation; need for additional corticosteroids; and clinical performance measures, such as dyspnea score and quality of life) also did not differ between groups. Nor were there differences in hyperglycemia, worsening hypertension, infection, or other adverse effects typically associated with glucocorticoid use. The active treatment group took more than 400 mg more prednisone than the placebo group (mean, 793 mg vs 379 mg, respectively).

WHAT’S NEW?

Now we know: five days is enough

While randomized trials have found that glucocorticoids improve COPD symptoms, the optimal treatment dose and duration were not known. Indeed, current guidelines recommend treatment for more than five days.³ This trial clearly demonstrated that 40-mg prednisone for five days is at least as good as a 14-day treatment course. Furthermore, it is un­necessary to taper the short-course therapy, which simplifies the regimen.

CAVEATS

Will the results apply to those less severely ill?

More than 80% of patients with acute COPD exacerbations can be managed in an outpatient setting.³ However, participants in this trial were hospitalized for a median of 8.5 days, and most had severe or very severe COPD—and thus, were not fully representative of COPD patients typically seen in an outpatient practice. Yet patients with less severe disease should be at least as likely to ­respond to short-course steroids as those whose COPD is more ­severe.

It is important to note that participants in this study all received optimal guideline-based therapies during hospitalization, which may be difficult to achieve for some patients treated in an outpatient setting. Finally, treatment adherence observed during the hospitalization period in this trial is unlikely to be replicated in the outpatient setting.

CHALLENGES TO IMPLEMENTATION

Identifying patients who need steroids for a longer duration

For patients with new COPD exacerbations or those successfully treated using short-course therapy in the past, a five-day regimen may be appropriate. For those in whom prior attempts at short-course treatment have failed, however, a 14-day course of treatment may be more advisable. That said, no guidelines are available to help us determine which patients previously treated with a longer regimen will find the shorter course of treatment unsuccessful.

Continue for references...

REFERENCES

1. Leuppi JD, Schuetz P, Bingisser R, et al. Short-term vs conventional glucocorticoid therapy in acute exacerbations of chronic obstructive pulmonary disease: the REDUCE randomized clinical trial. JAMA. 2013;309:2223-2231.

2. Soler-Cataluna JJ, Martinez-Garcia MA, Roman Sanchez P, et al. Severe acute exacerbations and mortality in patients with chronic obstructive pulmonary disease. Thorax. 2005;60:925-931.

3. Global Initiative for Chronic Obstructive Lung Disease, Inc. The global strategy for diagnosis, management, and prevention of chronic obstructive pulmonary disease. www.goldcopd.org. Accessed January 9, 2014.

4. Quon BS, Gan WQ, Sin DD. Contemporary management of acute exacerbations of COPD: a systematic review and metaanalysis. Chest. 2008;133:756-766.

5. Walters JA, Wang W, Morley C, et al. Different durations of corticosteroid therapy for exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2011; (10):CD006897.

6. Niewoehner DE, Erbland ML, Deupree RH, et al. Effect of systemic glucocorticoids on exacerbations of chronic obstructive pulmonary disease. Department of Veterans Affairs Cooperative Study Group. N Engl J Med. 1999;340:1941-1947.

ACKNOWLEDGEMENT

The PURLs Surveillance System is supported in part by Grant Number UL 1RR 024999 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(1):29-30, 32.

PRACTICE CHANGER

Prescribe a five-day regimen of glucocorticoid therapy for acute exacerbations of chronic obstructive pulmonary disease (COPD); the shorter course of treatment appears to be as effective as a 14-day regimen.¹

Strength of ­recommendation

B: Based on a single well-­designed randomized controlled trial (RCT).¹

ILLUSTRATIVE CASE

A 55-year-old man with COPD presents to the emergency department (ED) with progressive shortness of breath, cough, and sputum production in the past four days. He is diagnosed with a COPD exacerbation, treated with corticosteroids, and admitted to the hospital. His inpatient treatment includes antibiotics, inhaled albuterol and ipratropium, supplemental oxygen, and oral corticosteroids.

How many days should he take oral steroids?

Severe exacerbations of COPD are independently associated with mortality,² regardless of baseline severity. Guidelines and systematic reviews highlight the importance of using oral glucocorticoids in the management of acute COPD exacerbations, as the drugs have been found to shorten recovery time and length of hospital stay, improve lung function, and reduce the risk for early relapse and treatment failure.^3-5 What is not clear is how long the course of oral steroids should be.

What we know (and don’t know) about duration

Data supporting a 14-day course of steroids versus a longer (eight-week) duration come from the Systemic Corticosteroids in COPD Exacerbations trial.⁶ Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria suggest a 10- to 14-day regimen (30 to 40 mg/d) but acknowledge that there is a lack of data from clinical and observational studies to support this recommendation.³ A recent Cochrane review compared a short course of treatment (three to seven days) with a longer regimen (10 to 15 days) and found that the evidence to support a clinical practice change was inconclusive.⁵

The study detailed in this PURL—a double-blind RCT comparing five-day with 14-day oral steroid treatment in patients ­hospitalized for acute COPD exacerbation—had more definitive results.¹

Continue reading for the study summary...

STUDY SUMMARY

Shorter and longer regimens produce equal results

Leuppi et al¹ used noninferiority methodology to compare a five- and a 14-day course of prednisone 40 mg/d to treat patients with COPD exacerbations. A patient was considered to have an exacerbation if he or she had a change from baseline in two or more of the following: dyspnea, cough, sputum quantity, or purulence.

Participants were patients who presented to the EDs of five Swiss teaching hospitals between March 2006 and February 2011. To be eligible, individuals had to be 40 or older and have at least 20 pack-years of smoking. Exclusion criteria included asthma, mild obstruction (FEV₁/FVC > 70%), pneumonia, an estimated survival of less than six months, pregnancy, and lactation.

All the participants (N = 311) received 40 mg methylprednisolone intravenously on day 1, followed by prednisone 40 mg orally on days 2 through 5. The researchers then randomly divided participants into two groups: One group continued to take prednisone 40 mg/d and the other group received a matching placebo for an additional nine days. Participants in both groups also received antibiotics for seven days, twice-daily inhaled steroids, daily tiotropium, and nebulized albuterol, as needed; additional oral glucocorticoids could be administered, as well, at the discretion of the treating physicians.

The primary outcome was the time to the next COPD exacerbation, up to 180 days. Noninferiority between the groups was defined as no more than a 15% absolute increase in exacerbations. The dropout rate was 5.7%, evenly divided between groups. Intention to treat and per-protocol analyses were conducted, and hazard ratios (HRs) were calculated using the Kaplan-Meier method and Cox proportional hazards models.

The time to next COPD exacerbation did not differ between the study groups: 56 days for those on the five-day steroid regimen versus 57 days for those on the
14-day regimen in the intention-to-treat analysis (HR, 0.95). Sensitivity analyses adjusting for baseline characteristics provided similar results, as did the per-protocol analysis.

Secondary outcomes (overall survival; need for mechanical ventilation; need for additional corticosteroids; and clinical performance measures, such as dyspnea score and quality of life) also did not differ between groups. Nor were there differences in hyperglycemia, worsening hypertension, infection, or other adverse effects typically associated with glucocorticoid use. The active treatment group took more than 400 mg more prednisone than the placebo group (mean, 793 mg vs 379 mg, respectively).

WHAT’S NEW?

Now we know: five days is enough

While randomized trials have found that glucocorticoids improve COPD symptoms, the optimal treatment dose and duration were not known. Indeed, current guidelines recommend treatment for more than five days.³ This trial clearly demonstrated that 40-mg prednisone for five days is at least as good as a 14-day treatment course. Furthermore, it is un­necessary to taper the short-course therapy, which simplifies the regimen.

CAVEATS

Will the results apply to those less severely ill?

More than 80% of patients with acute COPD exacerbations can be managed in an outpatient setting.³ However, participants in this trial were hospitalized for a median of 8.5 days, and most had severe or very severe COPD—and thus, were not fully representative of COPD patients typically seen in an outpatient practice. Yet patients with less severe disease should be at least as likely to ­respond to short-course steroids as those whose COPD is more ­severe.

It is important to note that participants in this study all received optimal guideline-based therapies during hospitalization, which may be difficult to achieve for some patients treated in an outpatient setting. Finally, treatment adherence observed during the hospitalization period in this trial is unlikely to be replicated in the outpatient setting.

CHALLENGES TO IMPLEMENTATION

Identifying patients who need steroids for a longer duration

For patients with new COPD exacerbations or those successfully treated using short-course therapy in the past, a five-day regimen may be appropriate. For those in whom prior attempts at short-course treatment have failed, however, a 14-day course of treatment may be more advisable. That said, no guidelines are available to help us determine which patients previously treated with a longer regimen will find the shorter course of treatment unsuccessful.

Continue for references...

REFERENCES

1. Leuppi JD, Schuetz P, Bingisser R, et al. Short-term vs conventional glucocorticoid therapy in acute exacerbations of chronic obstructive pulmonary disease: the REDUCE randomized clinical trial. JAMA. 2013;309:2223-2231.

2. Soler-Cataluna JJ, Martinez-Garcia MA, Roman Sanchez P, et al. Severe acute exacerbations and mortality in patients with chronic obstructive pulmonary disease. Thorax. 2005;60:925-931.

3. Global Initiative for Chronic Obstructive Lung Disease, Inc. The global strategy for diagnosis, management, and prevention of chronic obstructive pulmonary disease. www.goldcopd.org. Accessed January 9, 2014.

4. Quon BS, Gan WQ, Sin DD. Contemporary management of acute exacerbations of COPD: a systematic review and metaanalysis. Chest. 2008;133:756-766.

5. Walters JA, Wang W, Morley C, et al. Different durations of corticosteroid therapy for exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2011; (10):CD006897.

6. Niewoehner DE, Erbland ML, Deupree RH, et al. Effect of systemic glucocorticoids on exacerbations of chronic obstructive pulmonary disease. Department of Veterans Affairs Cooperative Study Group. N Engl J Med. 1999;340:1941-1947.

ACKNOWLEDGEMENT

The PURLs Surveillance System is supported in part by Grant Number UL 1RR 024999 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(1):29-30, 32.

Illustrative case

A 55-year-old man with COPD presents to the emergency department (ED) because of progressive shortness of breath, cough, and sputum production over the past 4 days. He is diagnosed with a COPD exacerbation, treated with corticosteroids, and admitted to the hospital. His inpatient treatment includes antibiotics, inhaled albuterol and ipratropium, supplemental oxygen, and oral corticosteroids.

How many days should he take oral steroids?

Severe exacerbations of COPD are independently associated with mortality,² regardless of baseline severity. Guidelines and systematic reviews highlight the importance of using oral glucocorticoids in the management of acute COPD exacerbations, as the drugs have been found to shorten recovery time and length of hospital stay, improve lung function, and reduce the risk of early relapse and treatment failure.^3-5 What is not clear is how long the course of oral steroids should be.

What we know (and don’t know) about duration

Data supporting a 14-day course of steroids vs a longer (8-week) duration comes from the Systemic Corticosteroids in COPD Exacerbations trial.⁶ Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria suggest a 10- to-14-day regimen (30-40 mg/d), but acknowledge that there is a lack of data from clinical and observational studies to support this recommendation.³ A recent Cochrane review compared a short course of treatment (3-7 days) with a longer regimen (10-15 days) and found that the evidence to support a clinical practice change was inconclusive.⁵

The study detailed in this PURL—a double-blind RCT comparing 5-day with 14-day oral steroid treatment in patients hospitalized for acute COPD exacerbation—had more definitive results.¹

STUDY SUMMARY: Shorter and longer regimens produce equal results

Leuppi et al¹ used noninferiority methodology to compare a 5- vs a 14-day course of prednisone (40 mg/d) to treat patients with COPD exacerbations. A patient was considered to have a COPD exacerbation if he or she had a change from baseline in ≥2 of the following: dyspnea, cough, sputum quantity, or purulence.

Participants were patients who came to the EDs of 5 Swiss teaching hospitals between March 2006 and February 2011. To be eligible, individuals had to be 40 years or older and have ≥20 pack-years of smoking. Exclusion criteria included asthma, mild obstruction (forced expiratory volume in one second/forced vital capacity >70%), pneumonia, an estimated survival <6 months, pregnancy, and lactation.

All the participants (N=311) received 40 mg methylprednisolone intravenously on Day 1, followed by prednisone 40 mg orally on Days 2 through 5. The researchers then randomly divided participants into 2 groups: One group continued to take prednisone 40 mg/d and the other group received a matching placebo for an additional 9 days. Participants in both groups also received antibiotics for 7 days, twice daily inhaled steroids, daily tiotropium, and nebulized albuterol, as needed; additional oral glucocorticoids could be administered, as well, at the discretion of the treating physicians.

This trial clearly demonstrated that 40 mg prednisone for 5 days is at least as good as a 14-day regimen. What's more, it is not necessary to taper the short-course therapy, which simplifies treatment. The primary outcome was the time to the next COPD exacerbation, up to 180 days. Noninferiority between the groups was defined as no more than a 15% absolute increase in exacerbations. The dropout rate was 5.7%, evenly divided between groups. Intention to treat and per-protocol analyses were conducted, and hazard ratios (HRs) were calculated using the Kaplan-Meier method and Cox proportional hazards models.

The time to next COPD exacerbation did not differ between the study groups: 56 days for those on the 5-day steroid regimen vs 57 days for those on the 14-day regimen in the intention to treat analysis (HR=0.95; 90% confidence interval, 0.70-1.29; P=.006). Sensitivity analyses adjusting for baseline characteristics provided similar results, as did the per-protocol analysis.

Secondary outcomes (overall survival; need for mechanical ventilation; need for additional corticosteroids; and clinical performance measures, such as dyspnea score and quality of life) also did not differ between groups. Nor were there differences in hyperglycemia, worsening hypertension, infection, or other adverse effects typically associated with glucocorticoid use. The active treatment group took >400 mg more prednisone than the placebo group (mean, 793 mg vs 379 mg; P<.001).

WHAT'S NEW?: Now we know: 5 days is enough

While randomized trials have found that glucocorticoids improve COPD symptoms, the optimal treatment dose and duration were not known. Indeed, current guidelines recommend treatment for >5 days.³ This trial clearly demonstrated that 40 mg prednisone for 5 days is at least as good as a 14-day treatment course. Furthermore, it is unnecessary to taper the short-course therapy, which simplifies the regimen.

CAVEATS: Will the results apply to those less severely ill?

More than 80% of patients with acute COPD exacerbations can be managed in an outpatient setting.³ However, participants in this trial were hospitalized for a median of 8.5 days, and most had severe or very severe COPD—and thus, were not fully representative of COPD patients typically seen in an outpatient practice. Yet patients with less severe disease should be at least as likely to respond to short-course steroids as those whose COPD is more severe.

It is important to note that participants in this study all received optimal guideline-based therapies during hospitalization, which may be difficult to achieve for some patients treated in an outpatient setting. Finally, treatment adherence observed during the hospitalization period in this trial is unlikely to be replicated in the outpatient setting.

CHALLENGES TO IMPLEMENTATION: Identifying patients who need steroids for a longer duration

For patients with new COPD exacerbations or those successfully treated using short-course therapy in the past, a 5-day regimen may be appropriate. For those who have failed prior attempts at short-course treatment, however, a 14-day course of treatment may be more advisable. That said, no guidelines are available to help us determine which of those who were previously treated with a longer regimen may fail on the shorter course of treatment.

Acknowledgement

The PURLs Surveillance System is supported in part by Grant Number UL 1RR 024999 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 55-year-old man with COPD presents to the emergency department (ED) because of progressive shortness of breath, cough, and sputum production over the past 4 days. He is diagnosed with a COPD exacerbation, treated with corticosteroids, and admitted to the hospital. His inpatient treatment includes antibiotics, inhaled albuterol and ipratropium, supplemental oxygen, and oral corticosteroids.

How many days should he take oral steroids?

Severe exacerbations of COPD are independently associated with mortality,² regardless of baseline severity. Guidelines and systematic reviews highlight the importance of using oral glucocorticoids in the management of acute COPD exacerbations, as the drugs have been found to shorten recovery time and length of hospital stay, improve lung function, and reduce the risk of early relapse and treatment failure.^3-5 What is not clear is how long the course of oral steroids should be.

What we know (and don’t know) about duration

Data supporting a 14-day course of steroids vs a longer (8-week) duration comes from the Systemic Corticosteroids in COPD Exacerbations trial.⁶ Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria suggest a 10- to-14-day regimen (30-40 mg/d), but acknowledge that there is a lack of data from clinical and observational studies to support this recommendation.³ A recent Cochrane review compared a short course of treatment (3-7 days) with a longer regimen (10-15 days) and found that the evidence to support a clinical practice change was inconclusive.⁵

The study detailed in this PURL—a double-blind RCT comparing 5-day with 14-day oral steroid treatment in patients hospitalized for acute COPD exacerbation—had more definitive results.¹

STUDY SUMMARY: Shorter and longer regimens produce equal results

Leuppi et al¹ used noninferiority methodology to compare a 5- vs a 14-day course of prednisone (40 mg/d) to treat patients with COPD exacerbations. A patient was considered to have a COPD exacerbation if he or she had a change from baseline in ≥2 of the following: dyspnea, cough, sputum quantity, or purulence.

Participants were patients who came to the EDs of 5 Swiss teaching hospitals between March 2006 and February 2011. To be eligible, individuals had to be 40 years or older and have ≥20 pack-years of smoking. Exclusion criteria included asthma, mild obstruction (forced expiratory volume in one second/forced vital capacity >70%), pneumonia, an estimated survival <6 months, pregnancy, and lactation.

All the participants (N=311) received 40 mg methylprednisolone intravenously on Day 1, followed by prednisone 40 mg orally on Days 2 through 5. The researchers then randomly divided participants into 2 groups: One group continued to take prednisone 40 mg/d and the other group received a matching placebo for an additional 9 days. Participants in both groups also received antibiotics for 7 days, twice daily inhaled steroids, daily tiotropium, and nebulized albuterol, as needed; additional oral glucocorticoids could be administered, as well, at the discretion of the treating physicians.

This trial clearly demonstrated that 40 mg prednisone for 5 days is at least as good as a 14-day regimen. What's more, it is not necessary to taper the short-course therapy, which simplifies treatment. The primary outcome was the time to the next COPD exacerbation, up to 180 days. Noninferiority between the groups was defined as no more than a 15% absolute increase in exacerbations. The dropout rate was 5.7%, evenly divided between groups. Intention to treat and per-protocol analyses were conducted, and hazard ratios (HRs) were calculated using the Kaplan-Meier method and Cox proportional hazards models.

The time to next COPD exacerbation did not differ between the study groups: 56 days for those on the 5-day steroid regimen vs 57 days for those on the 14-day regimen in the intention to treat analysis (HR=0.95; 90% confidence interval, 0.70-1.29; P=.006). Sensitivity analyses adjusting for baseline characteristics provided similar results, as did the per-protocol analysis.

Secondary outcomes (overall survival; need for mechanical ventilation; need for additional corticosteroids; and clinical performance measures, such as dyspnea score and quality of life) also did not differ between groups. Nor were there differences in hyperglycemia, worsening hypertension, infection, or other adverse effects typically associated with glucocorticoid use. The active treatment group took >400 mg more prednisone than the placebo group (mean, 793 mg vs 379 mg; P<.001).

WHAT'S NEW?: Now we know: 5 days is enough

While randomized trials have found that glucocorticoids improve COPD symptoms, the optimal treatment dose and duration were not known. Indeed, current guidelines recommend treatment for >5 days.³ This trial clearly demonstrated that 40 mg prednisone for 5 days is at least as good as a 14-day treatment course. Furthermore, it is unnecessary to taper the short-course therapy, which simplifies the regimen.

CAVEATS: Will the results apply to those less severely ill?

More than 80% of patients with acute COPD exacerbations can be managed in an outpatient setting.³ However, participants in this trial were hospitalized for a median of 8.5 days, and most had severe or very severe COPD—and thus, were not fully representative of COPD patients typically seen in an outpatient practice. Yet patients with less severe disease should be at least as likely to respond to short-course steroids as those whose COPD is more severe.

It is important to note that participants in this study all received optimal guideline-based therapies during hospitalization, which may be difficult to achieve for some patients treated in an outpatient setting. Finally, treatment adherence observed during the hospitalization period in this trial is unlikely to be replicated in the outpatient setting.

CHALLENGES TO IMPLEMENTATION: Identifying patients who need steroids for a longer duration

For patients with new COPD exacerbations or those successfully treated using short-course therapy in the past, a 5-day regimen may be appropriate. For those who have failed prior attempts at short-course treatment, however, a 14-day course of treatment may be more advisable. That said, no guidelines are available to help us determine which of those who were previously treated with a longer regimen may fail on the shorter course of treatment.

Acknowledgement

The PURLs Surveillance System is supported in part by Grant Number UL 1RR 024999 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 55-year-old man with COPD presents to the emergency department (ED) because of progressive shortness of breath, cough, and sputum production over the past 4 days. He is diagnosed with a COPD exacerbation, treated with corticosteroids, and admitted to the hospital. His inpatient treatment includes antibiotics, inhaled albuterol and ipratropium, supplemental oxygen, and oral corticosteroids.

How many days should he take oral steroids?

Severe exacerbations of COPD are independently associated with mortality,² regardless of baseline severity. Guidelines and systematic reviews highlight the importance of using oral glucocorticoids in the management of acute COPD exacerbations, as the drugs have been found to shorten recovery time and length of hospital stay, improve lung function, and reduce the risk of early relapse and treatment failure.^3-5 What is not clear is how long the course of oral steroids should be.

What we know (and don’t know) about duration

Data supporting a 14-day course of steroids vs a longer (8-week) duration comes from the Systemic Corticosteroids in COPD Exacerbations trial.⁶ Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria suggest a 10- to-14-day regimen (30-40 mg/d), but acknowledge that there is a lack of data from clinical and observational studies to support this recommendation.³ A recent Cochrane review compared a short course of treatment (3-7 days) with a longer regimen (10-15 days) and found that the evidence to support a clinical practice change was inconclusive.⁵

The study detailed in this PURL—a double-blind RCT comparing 5-day with 14-day oral steroid treatment in patients hospitalized for acute COPD exacerbation—had more definitive results.¹

STUDY SUMMARY: Shorter and longer regimens produce equal results

Leuppi et al¹ used noninferiority methodology to compare a 5- vs a 14-day course of prednisone (40 mg/d) to treat patients with COPD exacerbations. A patient was considered to have a COPD exacerbation if he or she had a change from baseline in ≥2 of the following: dyspnea, cough, sputum quantity, or purulence.

Participants were patients who came to the EDs of 5 Swiss teaching hospitals between March 2006 and February 2011. To be eligible, individuals had to be 40 years or older and have ≥20 pack-years of smoking. Exclusion criteria included asthma, mild obstruction (forced expiratory volume in one second/forced vital capacity >70%), pneumonia, an estimated survival <6 months, pregnancy, and lactation.

All the participants (N=311) received 40 mg methylprednisolone intravenously on Day 1, followed by prednisone 40 mg orally on Days 2 through 5. The researchers then randomly divided participants into 2 groups: One group continued to take prednisone 40 mg/d and the other group received a matching placebo for an additional 9 days. Participants in both groups also received antibiotics for 7 days, twice daily inhaled steroids, daily tiotropium, and nebulized albuterol, as needed; additional oral glucocorticoids could be administered, as well, at the discretion of the treating physicians.

This trial clearly demonstrated that 40 mg prednisone for 5 days is at least as good as a 14-day regimen. What's more, it is not necessary to taper the short-course therapy, which simplifies treatment. The primary outcome was the time to the next COPD exacerbation, up to 180 days. Noninferiority between the groups was defined as no more than a 15% absolute increase in exacerbations. The dropout rate was 5.7%, evenly divided between groups. Intention to treat and per-protocol analyses were conducted, and hazard ratios (HRs) were calculated using the Kaplan-Meier method and Cox proportional hazards models.

The time to next COPD exacerbation did not differ between the study groups: 56 days for those on the 5-day steroid regimen vs 57 days for those on the 14-day regimen in the intention to treat analysis (HR=0.95; 90% confidence interval, 0.70-1.29; P=.006). Sensitivity analyses adjusting for baseline characteristics provided similar results, as did the per-protocol analysis.

Secondary outcomes (overall survival; need for mechanical ventilation; need for additional corticosteroids; and clinical performance measures, such as dyspnea score and quality of life) also did not differ between groups. Nor were there differences in hyperglycemia, worsening hypertension, infection, or other adverse effects typically associated with glucocorticoid use. The active treatment group took >400 mg more prednisone than the placebo group (mean, 793 mg vs 379 mg; P<.001).

WHAT'S NEW?: Now we know: 5 days is enough

While randomized trials have found that glucocorticoids improve COPD symptoms, the optimal treatment dose and duration were not known. Indeed, current guidelines recommend treatment for >5 days.³ This trial clearly demonstrated that 40 mg prednisone for 5 days is at least as good as a 14-day treatment course. Furthermore, it is unnecessary to taper the short-course therapy, which simplifies the regimen.

CAVEATS: Will the results apply to those less severely ill?

More than 80% of patients with acute COPD exacerbations can be managed in an outpatient setting.³ However, participants in this trial were hospitalized for a median of 8.5 days, and most had severe or very severe COPD—and thus, were not fully representative of COPD patients typically seen in an outpatient practice. Yet patients with less severe disease should be at least as likely to respond to short-course steroids as those whose COPD is more severe.

It is important to note that participants in this study all received optimal guideline-based therapies during hospitalization, which may be difficult to achieve for some patients treated in an outpatient setting. Finally, treatment adherence observed during the hospitalization period in this trial is unlikely to be replicated in the outpatient setting.

CHALLENGES TO IMPLEMENTATION: Identifying patients who need steroids for a longer duration

For patients with new COPD exacerbations or those successfully treated using short-course therapy in the past, a 5-day regimen may be appropriate. For those who have failed prior attempts at short-course treatment, however, a 14-day course of treatment may be more advisable. That said, no guidelines are available to help us determine which of those who were previously treated with a longer regimen may fail on the shorter course of treatment.

Acknowledgement

The PURLs Surveillance System is supported in part by Grant Number UL 1RR 024999 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.