PURLs

Illustrative case

A 67-year-old woman with diabetes, hypertension, and hyperlipidemia comes to your office for an evaluation before undergoing a total hip arthroplasty. She is not taking a beta-blocker. Should you prescribe one?

Current guidelines from the American College of Cardiology Foundation (ACCF) and the American Heart Association (AHA) recommend starting beta-blockers to prevent cardiac events in patients about to undergo intermediate- or high-risk surgery or vascular surgery who have a history of inducible ischemia, coronary artery disease (CAD), or at least one risk factor for CAD.² However, the majority of the evidence for these guidelines, which were published in 2009 and are in the process of being updated, came from the DECREASE (Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography) trials, which have been discredited due to serious methodological flaws, including falsified descriptions of how outcomes were determined and fictitious databases.³ A new meta-analysis by Bouri et al¹ that excluded the DECREASE trials found that although preoperative beta-blockers reduce the rate of certain nonfatal outcomes, they increase the risk of death and stroke.

STUDY SUMMARY: Multiple RCTs find preop beta-blockers do more harm, than good

Bouri et al¹ conducted a meta-analysis of published RCTs evaluating preoperative beta-blockers vs placebo for patients undergoing noncardiac surgery. Of the 11 studies that met eligibility criteria, 2 were the discredited DECREASE trials. Thus, Bouri et al¹ analyzed 9 high-quality RCTs that included 10,529 patients.

Most studies included patients undergoing vascular surgery. Some studies also included intra-abdominal, intrathoracic, neurosurgical, orthopedic, urologic, and gynecologic surgeries. Beta-blockers were started no more than a day before surgery and were discontinued at hospital discharge or up to 30 days postop. Metoprolol was used in 5 trials, bisoprolol in one trial, atenolol in 2 trials, and propranolol in one trial. The primary endpoint was all-cause mortality within 30 days.

A total of 5264 patients were randomized to beta-blockers and 5265 to placebo. There were 162 deaths in the beta-blocker group and 129 deaths in the placebo group. Patients who received beta-blockers had a 27% increased risk of all-cause mortality (risk ratio [RR]=1.27; 95% confidence interval [CI], 1.01-1.60; P=.04). The number needed to harm was 160.

Six of the studies also evaluated rates of nonfatal myocardial infarction (MI), nonfatal stroke, and hypotension. Beta-blockers lowered the risk of nonfatal MI (RR=.73; 95% CI, .61-.88; P=.001), but increased the risk of nonfatal stroke (RR=1.73; 95% CI, 1.00-2.99; P=.05) and hypotension (RR=1.51; 95% CI, 1.37-1.67; P=.00001).

While beta-blockers protect against nonfatal MIs, they increase the risk of nonfatal strokes and death.This meta-analysis was dominated by the 2008 Peri-Operative ISchemic Evaluation (POISE) trial, an RCT that compared placebo to extended-release metoprolol, 100 mg 2 to 4 hours before surgery followed by 200 mg/d for 30 days, in 8351 patients with, or at risk for, atherosclerotic disease.⁴ While beta-blockers reduced the risk of MI and atrial fibrillation, they increased the risk of mortality and stroke, likely due to drug-induced hypotension. The slightly larger-than-typical doses of beta-blockers used in the POISE study may have contributed to the excess mortality.

WHAT'S NEW: Avoiding beta-blockers in surgery patients will prevent deaths

Bouri et al¹ found that while beta-blockers protect against nonfatal MIs, they increase the risk for nonfatal strokes and death. This new meta-analysis challenges the ACCF/AHA recommendations by suggesting that abandoning the use of beta-blockers for preoperative patients who aren’t already taking them will prevent a substantial number of perioperative deaths. Bouri et al¹ estimate that in the United Kingdom, where 47,286 deaths occur annually within 30 days of intermediate or high-risk procedures, the number of iatrogenic deaths would drop by approximately 10,000 if beta-blockers were not used.¹

CAVEATS: Don't stop beta-blockers in patients who already take them

This meta-analysis did not evaluate outcomes in patients who were already taking beta-blockers. Patients who are already on beta-blockers should continue to take them in the perioperative period, which is in line with current ACCF/AHA guidelines.

CHALLENGES TO IMPLEMENTATION: Some physician may be reluctant to disregard published guidelines 

Some physicians may not be comfortable ignoring the current ACCF/AHA guidelines that make a Class IIa recommendation (it is reasonable to administer this treatment) for the use of preoperative beta-blockade for patients at risk of cardiovascular events who were not previously taking a beta-blocker. This updated meta-analysis excludes the discredited DECREASE trials and challenges us to act against these current guidelines while we wait for updated recommendations.

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 67-year-old woman with diabetes, hypertension, and hyperlipidemia comes to your office for an evaluation before undergoing a total hip arthroplasty. She is not taking a beta-blocker. Should you prescribe one?

Current guidelines from the American College of Cardiology Foundation (ACCF) and the American Heart Association (AHA) recommend starting beta-blockers to prevent cardiac events in patients about to undergo intermediate- or high-risk surgery or vascular surgery who have a history of inducible ischemia, coronary artery disease (CAD), or at least one risk factor for CAD.² However, the majority of the evidence for these guidelines, which were published in 2009 and are in the process of being updated, came from the DECREASE (Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography) trials, which have been discredited due to serious methodological flaws, including falsified descriptions of how outcomes were determined and fictitious databases.³ A new meta-analysis by Bouri et al¹ that excluded the DECREASE trials found that although preoperative beta-blockers reduce the rate of certain nonfatal outcomes, they increase the risk of death and stroke.

STUDY SUMMARY: Multiple RCTs find preop beta-blockers do more harm, than good

Bouri et al¹ conducted a meta-analysis of published RCTs evaluating preoperative beta-blockers vs placebo for patients undergoing noncardiac surgery. Of the 11 studies that met eligibility criteria, 2 were the discredited DECREASE trials. Thus, Bouri et al¹ analyzed 9 high-quality RCTs that included 10,529 patients.

Most studies included patients undergoing vascular surgery. Some studies also included intra-abdominal, intrathoracic, neurosurgical, orthopedic, urologic, and gynecologic surgeries. Beta-blockers were started no more than a day before surgery and were discontinued at hospital discharge or up to 30 days postop. Metoprolol was used in 5 trials, bisoprolol in one trial, atenolol in 2 trials, and propranolol in one trial. The primary endpoint was all-cause mortality within 30 days.

A total of 5264 patients were randomized to beta-blockers and 5265 to placebo. There were 162 deaths in the beta-blocker group and 129 deaths in the placebo group. Patients who received beta-blockers had a 27% increased risk of all-cause mortality (risk ratio [RR]=1.27; 95% confidence interval [CI], 1.01-1.60; P=.04). The number needed to harm was 160.

Six of the studies also evaluated rates of nonfatal myocardial infarction (MI), nonfatal stroke, and hypotension. Beta-blockers lowered the risk of nonfatal MI (RR=.73; 95% CI, .61-.88; P=.001), but increased the risk of nonfatal stroke (RR=1.73; 95% CI, 1.00-2.99; P=.05) and hypotension (RR=1.51; 95% CI, 1.37-1.67; P=.00001).

While beta-blockers protect against nonfatal MIs, they increase the risk of nonfatal strokes and death.This meta-analysis was dominated by the 2008 Peri-Operative ISchemic Evaluation (POISE) trial, an RCT that compared placebo to extended-release metoprolol, 100 mg 2 to 4 hours before surgery followed by 200 mg/d for 30 days, in 8351 patients with, or at risk for, atherosclerotic disease.⁴ While beta-blockers reduced the risk of MI and atrial fibrillation, they increased the risk of mortality and stroke, likely due to drug-induced hypotension. The slightly larger-than-typical doses of beta-blockers used in the POISE study may have contributed to the excess mortality.

WHAT'S NEW: Avoiding beta-blockers in surgery patients will prevent deaths

Bouri et al¹ found that while beta-blockers protect against nonfatal MIs, they increase the risk for nonfatal strokes and death. This new meta-analysis challenges the ACCF/AHA recommendations by suggesting that abandoning the use of beta-blockers for preoperative patients who aren’t already taking them will prevent a substantial number of perioperative deaths. Bouri et al¹ estimate that in the United Kingdom, where 47,286 deaths occur annually within 30 days of intermediate or high-risk procedures, the number of iatrogenic deaths would drop by approximately 10,000 if beta-blockers were not used.¹

CAVEATS: Don't stop beta-blockers in patients who already take them

This meta-analysis did not evaluate outcomes in patients who were already taking beta-blockers. Patients who are already on beta-blockers should continue to take them in the perioperative period, which is in line with current ACCF/AHA guidelines.

CHALLENGES TO IMPLEMENTATION: Some physician may be reluctant to disregard published guidelines 

Some physicians may not be comfortable ignoring the current ACCF/AHA guidelines that make a Class IIa recommendation (it is reasonable to administer this treatment) for the use of preoperative beta-blockade for patients at risk of cardiovascular events who were not previously taking a beta-blocker. This updated meta-analysis excludes the discredited DECREASE trials and challenges us to act against these current guidelines while we wait for updated recommendations.

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 67-year-old woman with diabetes, hypertension, and hyperlipidemia comes to your office for an evaluation before undergoing a total hip arthroplasty. She is not taking a beta-blocker. Should you prescribe one?

Current guidelines from the American College of Cardiology Foundation (ACCF) and the American Heart Association (AHA) recommend starting beta-blockers to prevent cardiac events in patients about to undergo intermediate- or high-risk surgery or vascular surgery who have a history of inducible ischemia, coronary artery disease (CAD), or at least one risk factor for CAD.² However, the majority of the evidence for these guidelines, which were published in 2009 and are in the process of being updated, came from the DECREASE (Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography) trials, which have been discredited due to serious methodological flaws, including falsified descriptions of how outcomes were determined and fictitious databases.³ A new meta-analysis by Bouri et al¹ that excluded the DECREASE trials found that although preoperative beta-blockers reduce the rate of certain nonfatal outcomes, they increase the risk of death and stroke.

STUDY SUMMARY: Multiple RCTs find preop beta-blockers do more harm, than good

Bouri et al¹ conducted a meta-analysis of published RCTs evaluating preoperative beta-blockers vs placebo for patients undergoing noncardiac surgery. Of the 11 studies that met eligibility criteria, 2 were the discredited DECREASE trials. Thus, Bouri et al¹ analyzed 9 high-quality RCTs that included 10,529 patients.

Most studies included patients undergoing vascular surgery. Some studies also included intra-abdominal, intrathoracic, neurosurgical, orthopedic, urologic, and gynecologic surgeries. Beta-blockers were started no more than a day before surgery and were discontinued at hospital discharge or up to 30 days postop. Metoprolol was used in 5 trials, bisoprolol in one trial, atenolol in 2 trials, and propranolol in one trial. The primary endpoint was all-cause mortality within 30 days.

A total of 5264 patients were randomized to beta-blockers and 5265 to placebo. There were 162 deaths in the beta-blocker group and 129 deaths in the placebo group. Patients who received beta-blockers had a 27% increased risk of all-cause mortality (risk ratio [RR]=1.27; 95% confidence interval [CI], 1.01-1.60; P=.04). The number needed to harm was 160.

Six of the studies also evaluated rates of nonfatal myocardial infarction (MI), nonfatal stroke, and hypotension. Beta-blockers lowered the risk of nonfatal MI (RR=.73; 95% CI, .61-.88; P=.001), but increased the risk of nonfatal stroke (RR=1.73; 95% CI, 1.00-2.99; P=.05) and hypotension (RR=1.51; 95% CI, 1.37-1.67; P=.00001).

While beta-blockers protect against nonfatal MIs, they increase the risk of nonfatal strokes and death.This meta-analysis was dominated by the 2008 Peri-Operative ISchemic Evaluation (POISE) trial, an RCT that compared placebo to extended-release metoprolol, 100 mg 2 to 4 hours before surgery followed by 200 mg/d for 30 days, in 8351 patients with, or at risk for, atherosclerotic disease.⁴ While beta-blockers reduced the risk of MI and atrial fibrillation, they increased the risk of mortality and stroke, likely due to drug-induced hypotension. The slightly larger-than-typical doses of beta-blockers used in the POISE study may have contributed to the excess mortality.

WHAT'S NEW: Avoiding beta-blockers in surgery patients will prevent deaths

Bouri et al¹ found that while beta-blockers protect against nonfatal MIs, they increase the risk for nonfatal strokes and death. This new meta-analysis challenges the ACCF/AHA recommendations by suggesting that abandoning the use of beta-blockers for preoperative patients who aren’t already taking them will prevent a substantial number of perioperative deaths. Bouri et al¹ estimate that in the United Kingdom, where 47,286 deaths occur annually within 30 days of intermediate or high-risk procedures, the number of iatrogenic deaths would drop by approximately 10,000 if beta-blockers were not used.¹

CAVEATS: Don't stop beta-blockers in patients who already take them

This meta-analysis did not evaluate outcomes in patients who were already taking beta-blockers. Patients who are already on beta-blockers should continue to take them in the perioperative period, which is in line with current ACCF/AHA guidelines.

CHALLENGES TO IMPLEMENTATION: Some physician may be reluctant to disregard published guidelines 

Some physicians may not be comfortable ignoring the current ACCF/AHA guidelines that make a Class IIa recommendation (it is reasonable to administer this treatment) for the use of preoperative beta-blockade for patients at risk of cardiovascular events who were not previously taking a beta-blocker. This updated meta-analysis excludes the discredited DECREASE trials and challenges us to act against these current guidelines while we wait for updated recommendations.

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

PRACTICE CHANGER

Recommend 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

Consider antibiotics for patients with exacerbations of mild to moderate chronic obstructive pulmonary disease (COPD).¹

STRENGTH OF RECOMMENDATION

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

ILLUSTRATIVE CASE

A 45-year-old man with a history of mild COPD seeks treatment for worsening dyspnea and increased (nonpurulent) sputum production. He denies fever or chills. On exam, he has coarse breath sounds and scattered wheezes. Should you add antibiotics to his treatment?

COPD exacerbations—a worsening of symptoms beyond day-to-day variations that leads to a medication change—are part of the disease course and can accelerate lung function decline, decrease quality of life, and, when severe, increase mortality.² Infections cause an estimated 50% to 70% of COPD exacerbations.^2-4

Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines recommend using antibiotics to treat exacerbations in patients with moderate or severe COPD who

• Have increased dyspnea, sputum volume, and sputum purulence;

• Have two of these symptoms if increased sputum purulence is one of them; or

• Require mechanical ven­tilation.²

According to the GOLD guidelines, the choice of antibiotic should be based on local antibiograms; common options include amoxicillin, amoxicillin/clavulanate, azithromycin, and doxycycline.² Although the GOLD guidelines cover use of antibiotics for COPD exacerbations, this recommendation is based on analyses of studies that focused on patients with moderate or severe COPD.² There has been little research on using antibiotics for exacerbations of mild COPD.

STUDY SUMMARY

Using antibiotics often resolves symptoms

Llor et al¹ conducted a multicenter, double-blind, placebo-controlled RCT to examine the effectiveness of antibiotic treatment for COPD exacerbations. Participants (ages 40 and older) had mild to moderate COPD, defined as 10 or more pack-years of smoking, an FEV₁ greater than 50%, and an FEV₁/FVC ratio lower than 0.7. An exacerbation was defined as at least one of the following: increased dyspnea, increased sputum volume, or sputum purulence.

Patients were randomly assigned to receive amoxicillin/clavulanate 500/125 mg or placebo three times a day for eight days. Primary endpoints were clinical cure (resolution of symptoms) and clinical success (resolution or improvement of symptoms) at days 9 to 11, as determined by physician assessment. Secondary measures included cure and clinical success at day 20 and time until next exacerbation. Patients were monitored for one year after the exacerbation.

There were 162 patients in the antibiotic group and 156 in the placebo group; the two groups were demographically similar. In each group, four patients withdrew consent and were removed from analysis. By the 9-to-11-day follow-up visit, 74.1% of patients in the antibiotic group had clinical cure, compared with 59.9% in the placebo group (number needed to treat [NNT] = 7). Clinical success also was significantly greater with antibiotics compared with placebo (90.5% vs 80.9%).

The clinical cure rate at day 20 also was significantly greater in patients on antibiotics compared with placebo (81.6% vs 67.8%; NNT = 7). During the one-year follow-up, 58% of patients in the antibiotic group and 73.2% of those in the placebo group experienced additional exacerbations. Time to next exacerbation was significantly longer in patients taking antibiotics (233 days vs 160 days).

Can CRP level help determine who should receive antibiotics?

Previous studies have identified biomarkers, including C-reactive protein (CRP), that indicate COPD exacerbation but have not linked them to clinical course.^5-7 In this study, researchers measured CRP in patients receiving placebo to determine if this biomarker could predict clinical outcomes.

The researchers found that the clinical success rate among patients with a CRP lower than 40 mg/L was 87.6%, while only 34.5% of patients with a CRP greater than 40 mg/L experienced clinical success (sensitivity and specificity for clinical success at this cutoff were 0.655 and 0.876, respectively). This suggests that antibiotics might be appropriate for patients with an exacerbation of mild or moderate COPD who have a CRP greater than 40 mg/L.

There were 35 adverse events: 23 in the antibiotics group and 12 in the placebo group. Two patients in the antibiotics group discontinued treatment as a result. Most adverse events involved mild gastrointestinal problems.

Continued on next page >>

WHAT’S NEW?

Evidence supports antibiotics for mild to moderate COPD

Few placebo-controlled trials have addressed antibiotic use for exacerbations in patients with mild to moderate COPD.^2,8,9 This study demonstrated that, compared with placebo, symptom resolution and clinical success is greater with amoxicillin/clavulanate and that antibiotic treatment also may increase time until next exacerbation.

The study also looked at the relationship of CRP and exacerbations in the placebo group. Higher spontaneous clinical cure rates were noted when the CRP was lower than 40 mg/L.

CAVEATS

Effects of concomitant ­medications are unclear

In both the placebo and antibiotic groups, patients were taking other medications (including short- and long-acting β-agonists, anticholinergics, theophyllines, and oral or inhaled corticosteroids). Roughly the same number of patients in each group took additional medications, but researchers did not conduct a subgroup analysis to see if patients treated with these medications responded differently from those who received antibiotics alone.

GOLD guidelines already suggest antibiotics for exacerbations in patients with moderate COPD.² In this study, 89% of patients met criteria for moderate COPD and 11% for mild COPD. Though the percentage of patients who had mild COPD was small, we believe the results of this study warrant consideration of antibiotic use in patients with mild disease. Local antibiograms may show increased resistance to amoxicillin/clavulanate; this study did not address the use of other antibiotics.

CHALLENGES TO IMPLEMENTATION

Antibiotic overuse may be a concern

Concerns about antibiotic resistance may make clinicians reluctant to prescribe the drugs for those with mild to moderate COPD.      

REFERENCES

1. Llor C, Moragas A, Hernández S, et al. Efficacy of antibiotic therapy for acute exacerbations of mild to moderate chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2012;186(8):716-723.

2. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. January 2014. www.goldcopd.org/guidelines-global-strategy-for-diagnosis-management.html. Accessed April 15, 2014.

3. Donaldson GC, Seemungal TA, Bhowmik A, et al. Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease. Thorax. 2002;57(10):847-852.

4. Soler-Cataluña JJ, Martínez-García MA, Román Sánchez P, et al. Severe acute exacerbations and mortality in patients with chronic obstructive pulmonary disease. Thorax. 2005;60(11):925-931.

5. Vollenweider DJ, Jarrett H, Steurer-Stey CA, et al. Antibiotics for exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2012;12:CD010257.

6. Bartlett, JG, Sethi S. Management of infection in acute exacerbations of chronic obstructive pulmonary disease. In: Basow DS, ed. UpToDate. www.uptodate.com. Last updated March 27, 2012. Accessed January 2, 2013.

7. Lacoma A, Prat C, Andreo F, et al. Value of procalcitonin, C-reactive protein, and neopterin in exacerbations of chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis. 2011;6:157-169.

8. Antonescu-Turcu AL, Tomic R. C-reactive protein and copeptin: prognostic predictors in chronic obstructive pulmonary disease exacerbations. Curr Opin Pulm Med. 2009;15(2):120-125.

9. Thomsen M, Ingebrigtsen TS, Marott JL, et al. Inflammatory biomarkers and exacerbations in chronic obstructive pulmonary disease. JAMA. 2013;309(22):2353-2361.

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(4):E11-E13. 

PRACTICE CHANGER

Consider antibiotics for patients with exacerbations of mild to moderate chronic obstructive pulmonary disease (COPD).¹

STRENGTH OF RECOMMENDATION

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

ILLUSTRATIVE CASE

A 45-year-old man with a history of mild COPD seeks treatment for worsening dyspnea and increased (nonpurulent) sputum production. He denies fever or chills. On exam, he has coarse breath sounds and scattered wheezes. Should you add antibiotics to his treatment?

COPD exacerbations—a worsening of symptoms beyond day-to-day variations that leads to a medication change—are part of the disease course and can accelerate lung function decline, decrease quality of life, and, when severe, increase mortality.² Infections cause an estimated 50% to 70% of COPD exacerbations.^2-4

Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines recommend using antibiotics to treat exacerbations in patients with moderate or severe COPD who

• Have increased dyspnea, sputum volume, and sputum purulence;

• Have two of these symptoms if increased sputum purulence is one of them; or

• Require mechanical ven­tilation.²

According to the GOLD guidelines, the choice of antibiotic should be based on local antibiograms; common options include amoxicillin, amoxicillin/clavulanate, azithromycin, and doxycycline.² Although the GOLD guidelines cover use of antibiotics for COPD exacerbations, this recommendation is based on analyses of studies that focused on patients with moderate or severe COPD.² There has been little research on using antibiotics for exacerbations of mild COPD.

STUDY SUMMARY

Using antibiotics often resolves symptoms

Llor et al¹ conducted a multicenter, double-blind, placebo-controlled RCT to examine the effectiveness of antibiotic treatment for COPD exacerbations. Participants (ages 40 and older) had mild to moderate COPD, defined as 10 or more pack-years of smoking, an FEV₁ greater than 50%, and an FEV₁/FVC ratio lower than 0.7. An exacerbation was defined as at least one of the following: increased dyspnea, increased sputum volume, or sputum purulence.

Patients were randomly assigned to receive amoxicillin/clavulanate 500/125 mg or placebo three times a day for eight days. Primary endpoints were clinical cure (resolution of symptoms) and clinical success (resolution or improvement of symptoms) at days 9 to 11, as determined by physician assessment. Secondary measures included cure and clinical success at day 20 and time until next exacerbation. Patients were monitored for one year after the exacerbation.

There were 162 patients in the antibiotic group and 156 in the placebo group; the two groups were demographically similar. In each group, four patients withdrew consent and were removed from analysis. By the 9-to-11-day follow-up visit, 74.1% of patients in the antibiotic group had clinical cure, compared with 59.9% in the placebo group (number needed to treat [NNT] = 7). Clinical success also was significantly greater with antibiotics compared with placebo (90.5% vs 80.9%).

The clinical cure rate at day 20 also was significantly greater in patients on antibiotics compared with placebo (81.6% vs 67.8%; NNT = 7). During the one-year follow-up, 58% of patients in the antibiotic group and 73.2% of those in the placebo group experienced additional exacerbations. Time to next exacerbation was significantly longer in patients taking antibiotics (233 days vs 160 days).

Can CRP level help determine who should receive antibiotics?

Previous studies have identified biomarkers, including C-reactive protein (CRP), that indicate COPD exacerbation but have not linked them to clinical course.^5-7 In this study, researchers measured CRP in patients receiving placebo to determine if this biomarker could predict clinical outcomes.

The researchers found that the clinical success rate among patients with a CRP lower than 40 mg/L was 87.6%, while only 34.5% of patients with a CRP greater than 40 mg/L experienced clinical success (sensitivity and specificity for clinical success at this cutoff were 0.655 and 0.876, respectively). This suggests that antibiotics might be appropriate for patients with an exacerbation of mild or moderate COPD who have a CRP greater than 40 mg/L.

There were 35 adverse events: 23 in the antibiotics group and 12 in the placebo group. Two patients in the antibiotics group discontinued treatment as a result. Most adverse events involved mild gastrointestinal problems.

Continued on next page >>

WHAT’S NEW?

Evidence supports antibiotics for mild to moderate COPD

Few placebo-controlled trials have addressed antibiotic use for exacerbations in patients with mild to moderate COPD.^2,8,9 This study demonstrated that, compared with placebo, symptom resolution and clinical success is greater with amoxicillin/clavulanate and that antibiotic treatment also may increase time until next exacerbation.

The study also looked at the relationship of CRP and exacerbations in the placebo group. Higher spontaneous clinical cure rates were noted when the CRP was lower than 40 mg/L.

CAVEATS

Effects of concomitant ­medications are unclear

In both the placebo and antibiotic groups, patients were taking other medications (including short- and long-acting β-agonists, anticholinergics, theophyllines, and oral or inhaled corticosteroids). Roughly the same number of patients in each group took additional medications, but researchers did not conduct a subgroup analysis to see if patients treated with these medications responded differently from those who received antibiotics alone.

GOLD guidelines already suggest antibiotics for exacerbations in patients with moderate COPD.² In this study, 89% of patients met criteria for moderate COPD and 11% for mild COPD. Though the percentage of patients who had mild COPD was small, we believe the results of this study warrant consideration of antibiotic use in patients with mild disease. Local antibiograms may show increased resistance to amoxicillin/clavulanate; this study did not address the use of other antibiotics.

CHALLENGES TO IMPLEMENTATION

Antibiotic overuse may be a concern

Concerns about antibiotic resistance may make clinicians reluctant to prescribe the drugs for those with mild to moderate COPD.      

REFERENCES

1. Llor C, Moragas A, Hernández S, et al. Efficacy of antibiotic therapy for acute exacerbations of mild to moderate chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2012;186(8):716-723.

2. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. January 2014. www.goldcopd.org/guidelines-global-strategy-for-diagnosis-management.html. Accessed April 15, 2014.

3. Donaldson GC, Seemungal TA, Bhowmik A, et al. Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease. Thorax. 2002;57(10):847-852.

4. Soler-Cataluña JJ, Martínez-García MA, Román Sánchez P, et al. Severe acute exacerbations and mortality in patients with chronic obstructive pulmonary disease. Thorax. 2005;60(11):925-931.

5. Vollenweider DJ, Jarrett H, Steurer-Stey CA, et al. Antibiotics for exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2012;12:CD010257.

6. Bartlett, JG, Sethi S. Management of infection in acute exacerbations of chronic obstructive pulmonary disease. In: Basow DS, ed. UpToDate. www.uptodate.com. Last updated March 27, 2012. Accessed January 2, 2013.

7. Lacoma A, Prat C, Andreo F, et al. Value of procalcitonin, C-reactive protein, and neopterin in exacerbations of chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis. 2011;6:157-169.

8. Antonescu-Turcu AL, Tomic R. C-reactive protein and copeptin: prognostic predictors in chronic obstructive pulmonary disease exacerbations. Curr Opin Pulm Med. 2009;15(2):120-125.

9. Thomsen M, Ingebrigtsen TS, Marott JL, et al. Inflammatory biomarkers and exacerbations in chronic obstructive pulmonary disease. JAMA. 2013;309(22):2353-2361.

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(4):E11-E13. 

PRACTICE CHANGER

Consider antibiotics for patients with exacerbations of mild to moderate chronic obstructive pulmonary disease (COPD).¹

STRENGTH OF RECOMMENDATION

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

ILLUSTRATIVE CASE

A 45-year-old man with a history of mild COPD seeks treatment for worsening dyspnea and increased (nonpurulent) sputum production. He denies fever or chills. On exam, he has coarse breath sounds and scattered wheezes. Should you add antibiotics to his treatment?

COPD exacerbations—a worsening of symptoms beyond day-to-day variations that leads to a medication change—are part of the disease course and can accelerate lung function decline, decrease quality of life, and, when severe, increase mortality.² Infections cause an estimated 50% to 70% of COPD exacerbations.^2-4

Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines recommend using antibiotics to treat exacerbations in patients with moderate or severe COPD who

• Have increased dyspnea, sputum volume, and sputum purulence;

• Have two of these symptoms if increased sputum purulence is one of them; or

• Require mechanical ven­tilation.²

According to the GOLD guidelines, the choice of antibiotic should be based on local antibiograms; common options include amoxicillin, amoxicillin/clavulanate, azithromycin, and doxycycline.² Although the GOLD guidelines cover use of antibiotics for COPD exacerbations, this recommendation is based on analyses of studies that focused on patients with moderate or severe COPD.² There has been little research on using antibiotics for exacerbations of mild COPD.

STUDY SUMMARY

Using antibiotics often resolves symptoms

Llor et al¹ conducted a multicenter, double-blind, placebo-controlled RCT to examine the effectiveness of antibiotic treatment for COPD exacerbations. Participants (ages 40 and older) had mild to moderate COPD, defined as 10 or more pack-years of smoking, an FEV₁ greater than 50%, and an FEV₁/FVC ratio lower than 0.7. An exacerbation was defined as at least one of the following: increased dyspnea, increased sputum volume, or sputum purulence.

Patients were randomly assigned to receive amoxicillin/clavulanate 500/125 mg or placebo three times a day for eight days. Primary endpoints were clinical cure (resolution of symptoms) and clinical success (resolution or improvement of symptoms) at days 9 to 11, as determined by physician assessment. Secondary measures included cure and clinical success at day 20 and time until next exacerbation. Patients were monitored for one year after the exacerbation.

There were 162 patients in the antibiotic group and 156 in the placebo group; the two groups were demographically similar. In each group, four patients withdrew consent and were removed from analysis. By the 9-to-11-day follow-up visit, 74.1% of patients in the antibiotic group had clinical cure, compared with 59.9% in the placebo group (number needed to treat [NNT] = 7). Clinical success also was significantly greater with antibiotics compared with placebo (90.5% vs 80.9%).

The clinical cure rate at day 20 also was significantly greater in patients on antibiotics compared with placebo (81.6% vs 67.8%; NNT = 7). During the one-year follow-up, 58% of patients in the antibiotic group and 73.2% of those in the placebo group experienced additional exacerbations. Time to next exacerbation was significantly longer in patients taking antibiotics (233 days vs 160 days).

Can CRP level help determine who should receive antibiotics?

Previous studies have identified biomarkers, including C-reactive protein (CRP), that indicate COPD exacerbation but have not linked them to clinical course.^5-7 In this study, researchers measured CRP in patients receiving placebo to determine if this biomarker could predict clinical outcomes.

The researchers found that the clinical success rate among patients with a CRP lower than 40 mg/L was 87.6%, while only 34.5% of patients with a CRP greater than 40 mg/L experienced clinical success (sensitivity and specificity for clinical success at this cutoff were 0.655 and 0.876, respectively). This suggests that antibiotics might be appropriate for patients with an exacerbation of mild or moderate COPD who have a CRP greater than 40 mg/L.

There were 35 adverse events: 23 in the antibiotics group and 12 in the placebo group. Two patients in the antibiotics group discontinued treatment as a result. Most adverse events involved mild gastrointestinal problems.

Continued on next page >>

WHAT’S NEW?

Evidence supports antibiotics for mild to moderate COPD

Few placebo-controlled trials have addressed antibiotic use for exacerbations in patients with mild to moderate COPD.^2,8,9 This study demonstrated that, compared with placebo, symptom resolution and clinical success is greater with amoxicillin/clavulanate and that antibiotic treatment also may increase time until next exacerbation.

The study also looked at the relationship of CRP and exacerbations in the placebo group. Higher spontaneous clinical cure rates were noted when the CRP was lower than 40 mg/L.

CAVEATS

Effects of concomitant ­medications are unclear

In both the placebo and antibiotic groups, patients were taking other medications (including short- and long-acting β-agonists, anticholinergics, theophyllines, and oral or inhaled corticosteroids). Roughly the same number of patients in each group took additional medications, but researchers did not conduct a subgroup analysis to see if patients treated with these medications responded differently from those who received antibiotics alone.

GOLD guidelines already suggest antibiotics for exacerbations in patients with moderate COPD.² In this study, 89% of patients met criteria for moderate COPD and 11% for mild COPD. Though the percentage of patients who had mild COPD was small, we believe the results of this study warrant consideration of antibiotic use in patients with mild disease. Local antibiograms may show increased resistance to amoxicillin/clavulanate; this study did not address the use of other antibiotics.

CHALLENGES TO IMPLEMENTATION

Antibiotic overuse may be a concern

Concerns about antibiotic resistance may make clinicians reluctant to prescribe the drugs for those with mild to moderate COPD.      

REFERENCES

1. Llor C, Moragas A, Hernández S, et al. Efficacy of antibiotic therapy for acute exacerbations of mild to moderate chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2012;186(8):716-723.

2. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. January 2014. www.goldcopd.org/guidelines-global-strategy-for-diagnosis-management.html. Accessed April 15, 2014.

3. Donaldson GC, Seemungal TA, Bhowmik A, et al. Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease. Thorax. 2002;57(10):847-852.

4. Soler-Cataluña JJ, Martínez-García MA, Román Sánchez P, et al. Severe acute exacerbations and mortality in patients with chronic obstructive pulmonary disease. Thorax. 2005;60(11):925-931.

5. Vollenweider DJ, Jarrett H, Steurer-Stey CA, et al. Antibiotics for exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2012;12:CD010257.

6. Bartlett, JG, Sethi S. Management of infection in acute exacerbations of chronic obstructive pulmonary disease. In: Basow DS, ed. UpToDate. www.uptodate.com. Last updated March 27, 2012. Accessed January 2, 2013.

7. Lacoma A, Prat C, Andreo F, et al. Value of procalcitonin, C-reactive protein, and neopterin in exacerbations of chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis. 2011;6:157-169.

8. Antonescu-Turcu AL, Tomic R. C-reactive protein and copeptin: prognostic predictors in chronic obstructive pulmonary disease exacerbations. Curr Opin Pulm Med. 2009;15(2):120-125.

9. Thomsen M, Ingebrigtsen TS, Marott JL, et al. Inflammatory biomarkers and exacerbations in chronic obstructive pulmonary disease. JAMA. 2013;309(22):2353-2361.

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(4):E11-E13. 

Illustrative case

A 45-year-old man with a history of mild COPD seeks treatment for worsening dyspnea and increased (nonpurulent) sputum production. He denies fever or chills. On exam, he has coarse breath sounds and scattered wheezes. Should you add antibiotics to his treatment?

COPD exacerbations—a worsening of symptoms beyond day-to-day variations that leads to a medication change—are part of the disease course and can accelerate lung function decline, decrease quality of life, and, when severe, increase mortality.² Infections cause an estimated 50% to 70% of COPD exacerbations.^2-4

Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines recommend using antibiotics to treat exacerbations in patients with moderate or severe COPD who:
• have increased dyspnea, sputum volume, and sputum purulence;
• have 2 of these 3 symptoms if increased sputum purulence is one of the symptoms; or
• require mechanical ventilation.²

According to the GOLD guidelines, the choice of antibiotic should be based on local antibiograms; common options include amoxicillin, amoxicillin/clavulanate, azithromycin, and doxycycline.² Although the GOLD guidelines cover use of antibiotics for COPD exacerbations, this recommendation is based on analyses of studies that focused on patients with moderate or severe COPD.² There has been little research on using antibiotics for exacerbations of mild COPD.

STUDY SUMMARY: Using antibiotics often resolves symptoms

Llor et al¹ conducted a multicenter, doubleblind placebo-controlled RCT to examine the effectiveness of antibiotic treatment for COPD exacerbations. Participants (ages ≥40 years) had mild to moderate COPD, defined as ≥10 pack-years of smoking, a forced expiratory volume in 1 second (FEV₁) >50%, and a FEV₁-to-forced vital capacity ratio <0.7. An exacerbation was defined as at least one of the following: increased dyspnea, increased sputum volume, or sputum purulence. Patients were randomized to receive amoxicillin/clavulanate 500/125 mg or placebo 3 times a day for 8 days. The primary endpoints were clinical cure (resolution of symptoms) and clinical success (resolution or improvement of symptoms) at Days 9 to 11 as determined by physician assessment. Secondary measures included cure and clinical success at Day 20 and time until next exacerbation. Patients were monitored for one year after the exacerbation.

There were 162 patients in the antibiotic group and 156 in the placebo group; the 2 groups were demographically similar. In each group, 4 patients withdrew consent and were removed from analysis. By the 9- to 11-day follow- up visit, 74.1% of patients in the antibiotic group had clinical cure, compared with 59.9% in the placebo group (P=.016; number needed to treat [NNT]=7). Clinical success also was significantly greater with antibiotics compared with placebo (90.5% vs 80.9%; P=.022).

By Day 11, symptoms resolved in 74.1% of patients in the antibiotic group, compared with 59.9% in the placebo group.The clinical cure rate at Day 20 also was significantly greater in patients on antibiotics compared with placebo (81.6% vs 67.8%; P=.006, NNT=7). During the one-year followup, 58% of patients in the antibiotic group and 73.2% of those in the placebo group experienced additional exacerbations. Time to next exacerbation was significantly longer in patients taking antibiotics (233 days vs 160 days; P=.015).

Can CRP level help determine who should—and shouldn’t—receive antibiotics? Previous studies have identified biomarkers, including C-reactive protein (CRP), that indicate COPD exacerbation, but have not linked them to clinical course.^5-7 In this study, researchers measured CRP in patients receiving placebo to determine if this biomarker could predict clinical outcomes.

The researchers found that the clinical success rate among patients with a CRP <40 mg/L was 87.6%, while only 34.5% of patients with a CRP >40 mg/L experienced clinical success (sensitivity and specificity for clinical success at this cutoff was 0.655 and 0.876, respectively). This suggests that antibiotics might be appropriate for patients with an exacerbation of mild or moderate COPD who have a CRP >40 mg/L.

A total of 35 adverse events were reported: 23 in patients taking antibiotics and 12 among patients receiving placebo. Only 2 patients discontinued treatment due to adverse events in antibiotics group. Most of these reactions were mild gastrointestinal problems.

WHAT'S NEW?: Evidence supports antibiotics for mild to moderate COPD

Few placebo-controlled trials have addressed antibiotic use for exacerbations in patients with mild to moderate COPD.^2,8,9 This study demonstrated that compared with placebo, symptom resolution and clinical success is greater with amoxicillin/clavulanate, and that antibiotic treatment also may increase time until next exacerbation.

The study also looked at the relationship of CRP and exacerbations in the placebo group. Higher spontaneous clinical cure rates were noted when the CRP was <40 mg/L.

CAVEATS: Effects of concomitant medications are unclear

In both the placebo and antibiotic groups, patients were taking other medications (including short-and long-acting beta-agonists, anticholinergics, theophyllines, and oral or inhaled corticosteroids). Roughly the same number of patients in each group took additional medications, but researchers did not conduct a subgroup analysis to see if patients treated with these medications responded differently than those who received antibiotics alone.

Clinical success also was significantly greater with antibiotics compared with placebo.GOLD guidelines already suggest antibiotics for exacerbations in patients with moderate COPD.² In this study, 89% of patients met criteria for moderate COPD and 11% for mild COPD. Though the percentage of patients who had mild COPD was small, we believe the results of this study warrant consideration of antibiotic use in patients with mild disease. Local antibiograms may show increased resistance to amoxicillin/clavulanate; this study did not address the use of other antibiotics.

CHALLENGES TO IMPLEMENTATION: Antibiotic overuse may be a concern

With increased awareness of inappropriate antibiotic use, physicians might have concerns about antibiotic resistance developing as a result of using antibiotics for exacerbations of mild to moderate COPD.

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 45-year-old man with a history of mild COPD seeks treatment for worsening dyspnea and increased (nonpurulent) sputum production. He denies fever or chills. On exam, he has coarse breath sounds and scattered wheezes. Should you add antibiotics to his treatment?

COPD exacerbations—a worsening of symptoms beyond day-to-day variations that leads to a medication change—are part of the disease course and can accelerate lung function decline, decrease quality of life, and, when severe, increase mortality.² Infections cause an estimated 50% to 70% of COPD exacerbations.^2-4

Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines recommend using antibiotics to treat exacerbations in patients with moderate or severe COPD who:
• have increased dyspnea, sputum volume, and sputum purulence;
• have 2 of these 3 symptoms if increased sputum purulence is one of the symptoms; or
• require mechanical ventilation.²

According to the GOLD guidelines, the choice of antibiotic should be based on local antibiograms; common options include amoxicillin, amoxicillin/clavulanate, azithromycin, and doxycycline.² Although the GOLD guidelines cover use of antibiotics for COPD exacerbations, this recommendation is based on analyses of studies that focused on patients with moderate or severe COPD.² There has been little research on using antibiotics for exacerbations of mild COPD.

STUDY SUMMARY: Using antibiotics often resolves symptoms

Llor et al¹ conducted a multicenter, doubleblind placebo-controlled RCT to examine the effectiveness of antibiotic treatment for COPD exacerbations. Participants (ages ≥40 years) had mild to moderate COPD, defined as ≥10 pack-years of smoking, a forced expiratory volume in 1 second (FEV₁) >50%, and a FEV₁-to-forced vital capacity ratio <0.7. An exacerbation was defined as at least one of the following: increased dyspnea, increased sputum volume, or sputum purulence. Patients were randomized to receive amoxicillin/clavulanate 500/125 mg or placebo 3 times a day for 8 days. The primary endpoints were clinical cure (resolution of symptoms) and clinical success (resolution or improvement of symptoms) at Days 9 to 11 as determined by physician assessment. Secondary measures included cure and clinical success at Day 20 and time until next exacerbation. Patients were monitored for one year after the exacerbation.

There were 162 patients in the antibiotic group and 156 in the placebo group; the 2 groups were demographically similar. In each group, 4 patients withdrew consent and were removed from analysis. By the 9- to 11-day follow- up visit, 74.1% of patients in the antibiotic group had clinical cure, compared with 59.9% in the placebo group (P=.016; number needed to treat [NNT]=7). Clinical success also was significantly greater with antibiotics compared with placebo (90.5% vs 80.9%; P=.022).

By Day 11, symptoms resolved in 74.1% of patients in the antibiotic group, compared with 59.9% in the placebo group.The clinical cure rate at Day 20 also was significantly greater in patients on antibiotics compared with placebo (81.6% vs 67.8%; P=.006, NNT=7). During the one-year followup, 58% of patients in the antibiotic group and 73.2% of those in the placebo group experienced additional exacerbations. Time to next exacerbation was significantly longer in patients taking antibiotics (233 days vs 160 days; P=.015).

Can CRP level help determine who should—and shouldn’t—receive antibiotics? Previous studies have identified biomarkers, including C-reactive protein (CRP), that indicate COPD exacerbation, but have not linked them to clinical course.^5-7 In this study, researchers measured CRP in patients receiving placebo to determine if this biomarker could predict clinical outcomes.

The researchers found that the clinical success rate among patients with a CRP <40 mg/L was 87.6%, while only 34.5% of patients with a CRP >40 mg/L experienced clinical success (sensitivity and specificity for clinical success at this cutoff was 0.655 and 0.876, respectively). This suggests that antibiotics might be appropriate for patients with an exacerbation of mild or moderate COPD who have a CRP >40 mg/L.

A total of 35 adverse events were reported: 23 in patients taking antibiotics and 12 among patients receiving placebo. Only 2 patients discontinued treatment due to adverse events in antibiotics group. Most of these reactions were mild gastrointestinal problems.

WHAT'S NEW?: Evidence supports antibiotics for mild to moderate COPD

Few placebo-controlled trials have addressed antibiotic use for exacerbations in patients with mild to moderate COPD.^2,8,9 This study demonstrated that compared with placebo, symptom resolution and clinical success is greater with amoxicillin/clavulanate, and that antibiotic treatment also may increase time until next exacerbation.

The study also looked at the relationship of CRP and exacerbations in the placebo group. Higher spontaneous clinical cure rates were noted when the CRP was <40 mg/L.

CAVEATS: Effects of concomitant medications are unclear

In both the placebo and antibiotic groups, patients were taking other medications (including short-and long-acting beta-agonists, anticholinergics, theophyllines, and oral or inhaled corticosteroids). Roughly the same number of patients in each group took additional medications, but researchers did not conduct a subgroup analysis to see if patients treated with these medications responded differently than those who received antibiotics alone.

Clinical success also was significantly greater with antibiotics compared with placebo.GOLD guidelines already suggest antibiotics for exacerbations in patients with moderate COPD.² In this study, 89% of patients met criteria for moderate COPD and 11% for mild COPD. Though the percentage of patients who had mild COPD was small, we believe the results of this study warrant consideration of antibiotic use in patients with mild disease. Local antibiograms may show increased resistance to amoxicillin/clavulanate; this study did not address the use of other antibiotics.

CHALLENGES TO IMPLEMENTATION: Antibiotic overuse may be a concern

With increased awareness of inappropriate antibiotic use, physicians might have concerns about antibiotic resistance developing as a result of using antibiotics for exacerbations of mild to moderate COPD.

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 45-year-old man with a history of mild COPD seeks treatment for worsening dyspnea and increased (nonpurulent) sputum production. He denies fever or chills. On exam, he has coarse breath sounds and scattered wheezes. Should you add antibiotics to his treatment?

COPD exacerbations—a worsening of symptoms beyond day-to-day variations that leads to a medication change—are part of the disease course and can accelerate lung function decline, decrease quality of life, and, when severe, increase mortality.² Infections cause an estimated 50% to 70% of COPD exacerbations.^2-4

Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines recommend using antibiotics to treat exacerbations in patients with moderate or severe COPD who:
• have increased dyspnea, sputum volume, and sputum purulence;
• have 2 of these 3 symptoms if increased sputum purulence is one of the symptoms; or
• require mechanical ventilation.²

According to the GOLD guidelines, the choice of antibiotic should be based on local antibiograms; common options include amoxicillin, amoxicillin/clavulanate, azithromycin, and doxycycline.² Although the GOLD guidelines cover use of antibiotics for COPD exacerbations, this recommendation is based on analyses of studies that focused on patients with moderate or severe COPD.² There has been little research on using antibiotics for exacerbations of mild COPD.

STUDY SUMMARY: Using antibiotics often resolves symptoms

Llor et al¹ conducted a multicenter, doubleblind placebo-controlled RCT to examine the effectiveness of antibiotic treatment for COPD exacerbations. Participants (ages ≥40 years) had mild to moderate COPD, defined as ≥10 pack-years of smoking, a forced expiratory volume in 1 second (FEV₁) >50%, and a FEV₁-to-forced vital capacity ratio <0.7. An exacerbation was defined as at least one of the following: increased dyspnea, increased sputum volume, or sputum purulence. Patients were randomized to receive amoxicillin/clavulanate 500/125 mg or placebo 3 times a day for 8 days. The primary endpoints were clinical cure (resolution of symptoms) and clinical success (resolution or improvement of symptoms) at Days 9 to 11 as determined by physician assessment. Secondary measures included cure and clinical success at Day 20 and time until next exacerbation. Patients were monitored for one year after the exacerbation.

There were 162 patients in the antibiotic group and 156 in the placebo group; the 2 groups were demographically similar. In each group, 4 patients withdrew consent and were removed from analysis. By the 9- to 11-day follow- up visit, 74.1% of patients in the antibiotic group had clinical cure, compared with 59.9% in the placebo group (P=.016; number needed to treat [NNT]=7). Clinical success also was significantly greater with antibiotics compared with placebo (90.5% vs 80.9%; P=.022).

By Day 11, symptoms resolved in 74.1% of patients in the antibiotic group, compared with 59.9% in the placebo group.The clinical cure rate at Day 20 also was significantly greater in patients on antibiotics compared with placebo (81.6% vs 67.8%; P=.006, NNT=7). During the one-year followup, 58% of patients in the antibiotic group and 73.2% of those in the placebo group experienced additional exacerbations. Time to next exacerbation was significantly longer in patients taking antibiotics (233 days vs 160 days; P=.015).

Can CRP level help determine who should—and shouldn’t—receive antibiotics? Previous studies have identified biomarkers, including C-reactive protein (CRP), that indicate COPD exacerbation, but have not linked them to clinical course.^5-7 In this study, researchers measured CRP in patients receiving placebo to determine if this biomarker could predict clinical outcomes.

The researchers found that the clinical success rate among patients with a CRP <40 mg/L was 87.6%, while only 34.5% of patients with a CRP >40 mg/L experienced clinical success (sensitivity and specificity for clinical success at this cutoff was 0.655 and 0.876, respectively). This suggests that antibiotics might be appropriate for patients with an exacerbation of mild or moderate COPD who have a CRP >40 mg/L.

A total of 35 adverse events were reported: 23 in patients taking antibiotics and 12 among patients receiving placebo. Only 2 patients discontinued treatment due to adverse events in antibiotics group. Most of these reactions were mild gastrointestinal problems.

WHAT'S NEW?: Evidence supports antibiotics for mild to moderate COPD

Few placebo-controlled trials have addressed antibiotic use for exacerbations in patients with mild to moderate COPD.^2,8,9 This study demonstrated that compared with placebo, symptom resolution and clinical success is greater with amoxicillin/clavulanate, and that antibiotic treatment also may increase time until next exacerbation.

The study also looked at the relationship of CRP and exacerbations in the placebo group. Higher spontaneous clinical cure rates were noted when the CRP was <40 mg/L.

CAVEATS: Effects of concomitant medications are unclear

In both the placebo and antibiotic groups, patients were taking other medications (including short-and long-acting beta-agonists, anticholinergics, theophyllines, and oral or inhaled corticosteroids). Roughly the same number of patients in each group took additional medications, but researchers did not conduct a subgroup analysis to see if patients treated with these medications responded differently than those who received antibiotics alone.

Clinical success also was significantly greater with antibiotics compared with placebo.GOLD guidelines already suggest antibiotics for exacerbations in patients with moderate COPD.² In this study, 89% of patients met criteria for moderate COPD and 11% for mild COPD. Though the percentage of patients who had mild COPD was small, we believe the results of this study warrant consideration of antibiotic use in patients with mild disease. Local antibiograms may show increased resistance to amoxicillin/clavulanate; this study did not address the use of other antibiotics.

CHALLENGES TO IMPLEMENTATION: Antibiotic overuse may be a concern

With increased awareness of inappropriate antibiotic use, physicians might have concerns about antibiotic resistance developing as a result of using antibiotics for exacerbations of mild to moderate COPD.

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.