Study Authors: Christopher C. Butler, David Gillespie, et al.; Allan S. Brett, Majdi N. Al-Hasan
Target Audience and Goal Statement: Infectious disease specialists, pulmonologists, emergency physicians, hospitalists, primary care physicians
The goal was to find out if point-of-care-testing of C-reactive protein (CRP) might help lower unnecessary use of antibiotics without harming patients who have acute exacerbations of chronic obstructive pulmonary disease (COPD).
Question Addressed:
Did the addition of a CRP point-of-care test (with training on test use and advice on interpretation) to usual care for managing an acute exacerbation of COPD lead to a reduction in antibiotic use without negatively affecting COPD health status, versus usual care alone?
Action Points
- C-reaction protein (CRP)-guided prescribing of antibiotics for acute exacerbations of chronic obstructive pulmonary disease (COPD) in primary care clinics resulted in a lower percentage of patients who reported antibiotic use and who received antibiotic prescriptions from clinicians, with no evidence of harm.
- Realize the evidence suggests that CRP testing could be a useful adjunctive measure to guide antibiotic use in patients with acute exacerbations of COPD.
Study Synopsis and Perspective:
COPD is a disease of chronic airflow limitation characterized by a mixture of small airways disease and emphysema, the relative contributions of which can vary from person to person. According to the 2019 Global Initiative for Chronic Obstructive Lung Disease (GOLD) guide for healthcare professionals, the disease is common, preventable, and treatable. Yet COPD was listed as the third leading cause of death in the U.S. in 2014.
More than 6% of Americans have received a diagnosis of this condition, and about 2% of adults in the U.K. have a diagnosis of COPD in their primary care medical record. About half of affected individuals experience one or more acute exacerbations of COPD each year. Most such patients presenting with acute exacerbations in the primary care setting may receive an antibiotic, however, which may not always be the right treatment and may cause harm.
If CRP – a biomarker of inflammation that rises rapidly in the blood in response to serious infections — could be quickly measured at the point of care, that might predict who could benefit from treatment of acute exacerbations of COPD. But there was no evidence in the literature that the addition of such a test would lead to a reduction in antibiotic use without negatively affecting the health status of the patient.
Now, results from the multicenter, open-label, randomized, controlled PACE trial, which involved British patients with a diagnosis of COPD in their primary care clinical record and at least one of the Anthonisen criteria for acute exacerbations of COPD, have provided answers to those open questions. Christopher C. Butler, MD, of the University of Oxford in England, and colleagues reported in the New England Journal of Medicine that the trial met its objective of showing that CRP point-of-care testing could safely lower antibiotic use among participants.
Using the finger-prick blood test resulted in 20% fewer people using antibiotics for COPD flare-ups. Specifically, fewer patients in the CRP-guided group than the usual-care group received an antibiotic prescription at the initial consultation (47.7% vs 69.7%). Antibiotics were taken for COPD flares by 57% of people in the CRP-guided group and 77% of those in the usual-care group in the month following the initial consultation. Clinical outcomes were similar between the two trial groups.
At 6 months, prescribing and using less antibiotics continued showing no meaningful differences between the two trial groups with respect to healthcare–seeking behavior or measures of patient well-being. Similarly, no meaningful differences were seen between the two groups with respect to secondary clinical, microbiologic, disease-specific quality-of-life, or healthcare utilization with respect to primary and secondary care.
Findings from the PACE trial were based on an analysis of 325 patients randomized to the CRP-guided group and 324 to the usual-care group. Patient-reported use of antibiotics for acute exacerbations of COPD within 4 weeks after randomization (to show superiority) and COPD-related health status at 2 weeks after randomization, as measured by the Clinical COPD Questionnaire (CCQ), a 10-item scale with scores ranging from 0 (very good COPD health status) to 6 (extremely poor COPD health status), served as the primary outcomes.
Guidance was provided to physicians on the interpretation of CRP test results, “emphasizing that decisions about antibiotic prescribing should be based on a comprehensive assessment of likely risks and benefits, given a patient’s underlying health status and clinical features,” the researchers explained.
For the CRP-guided group, antibiotics were unlikely to be beneficial when the CRP level was lower than 20 mg per liter, when the CRP level was higher than 40 mg per liter, and possibly when the CRP level fell between these extremes and purulent sputum was present.
More than three quarters of patients (241 of 317; 76%) had CRP values lower than 20 mg per liter; 38 (12.0%) had CRP values 20-40 mg per liter, and 38 (12.0%) had CRP values higher than 40 mg per liter.
Overall, 57% of the CRP-guided group received antibiotics versus 77.4% in the usual-care group, the team noted.
Less antibiotic use and fewer prescriptions from physicians did not compromise patient-reported disease-specific quality of life, as noted by the fact that the between-group differences in the scores on the CCQ during follow-up were smaller than the published minimal clinically important difference of 0.4 (adjusted mean difference at 2 weeks was -0.19 [two-sided 90% CI, −0.33 to −0.05], favoring the CRP-guided group).
No evidence of a clinically important between-group difference in adverse effects from antibiotics (adjusted odds ratio, 0.79; 95% CI 0.44 -1.39) was seen by the researchers; two patients in the usual-care group died within 4 weeks after randomization from causes considered to be unrelated to trial participation, Butler, et al. said.
They noted that adding sham tests to the usual-care group might have taken into account the contribution of awareness of a point-of-care test to enhanced COPD-related health status. Nevertheless, Butler’s group noted that this real-world effect needed to be captured because it may have affected health care–seeking behavior, which was critical to assessments of overall benefit.
Source Reference: New England Journal of Medicine 2019; 381: 111-120
Editorial: New England Journal of Medicine 2019; 381: 174-175
Study Highlights and Explanation of Findings:
Among 653 patients enrolled in the PACE trial, the percentage of patients who reported using antibiotics within 4 weeks after randomization was significantly lower in the CRP-guided group than in the control group (57% vs 77%).
“This rigorous clinical trial speaks directly to the pressing issues of preserving the usefulness of our existing antibiotics; the potential of stratified, personalized care; the importance of contextually appropriate evidence about point-of-care testing in reducing unnecessary antibiotic use; and enhancing the quality of care for people with the common condition of chronic obstructive pulmonary disease,” Butler said in a press statement.
“Most antibiotics are prescribed in primary medical care, and many of these prescriptions do not benefit patients: point-of-care testing is being vigorously promoted as a critical solution for better targeted antibiotic prescribing,” he continued. “However, there have been virtually no trials of point-of-care tests that measure impact on clinician behavior, patient behavior, and patient outcomes.”
“Acute exacerbations of COPD account for a considerable proportion of unnecessary antibiotic use, but a good solution to the problem in ambulatory care (where most of the antibiotics are prescribed) has not been identified until now,” Butler said. “Ours is the first trial of biomarker guided management of acute exacerbations of COPD in ambulatory care, and has found an effect that should be practice-changing.”
Writing in an accompanying editorial, Allan S. Brett, MD, and Majdi N. Al-Hasan, MBBS, both of the University of South Carolina School of Medicine in Columbia, explained that historically, antibiotic therapy for patients with acute exacerbations of COPD was guided by Anthonisen criteria (i.e., increased dyspnea and sputum volume and sputum purulence). Based on one trial, conducted 30 years ago, treatment success, which occurred among more patients who received antibiotics than among those who received placebo (68% vs 55%), was confined largely to those who had at least two of the three criteria.
Taken together with other contradictory studies from the literature, the results from previous studies remain “muddled,” Brett and Al-Hasan said. By contrast, the PACE findings are “compelling enough to support CRP testing as an adjunctive measure to guide antibiotic use in patients with acute exacerbations of COPD.”
The editorialists noted that antibiotic exposure predisposes patients to airway colonization by multi-drug resistant bacteria, which could lead to pneumonia in vulnerable patients with COPD. Additionally, antibiotic use has been associated with risks of adverse events such as Clostridioides difficile colitis. Therefore, reducing the use of antibiotics probably conferred both immediate and delayed benefits in this patient population, Brett and Al-Hasan theorized.
However, while the trial suggested a way to lower antibiotic prescribing without compromising clinical outcomes, the editorialists noted that the findings did not establish which patients would benefit from antibiotic therapy or which antibiotics were most appropriate for acute exacerbations of COPD.