Effect of Ipratropium on Acute Bronchitis in Subjects Without Underlying Lung Disease

Condition(s) targeted: Bronchitis

Intervention: ipratropium (Drug)

Phase: N/A

Status: Completed

Sponsored by: Kaiser Permanente

Official(s) and/or principal investigator(s):
Thomas B McIlraith, MD, Principal Investigator, Affiliation: Mercy Medical Group
Norman Chow, MD, Principal Investigator, Affiliation: Kaiser Permanente

ABSTRACT CONTEXT: Inappropriate antibiotic prescriptions for acute bronchitis is a major public health concern because of antibiotic resistance. Effective therapies for managing the symptoms of acute bronchitis are lacking, however.

OBJECTIVE: Determine if patients with acute bronchitis have better symptom control when treated with inhaled ipratropium.

DESIGN, SETTING, PARTICIPANTS: COUGH STOP was a randomized, double blind, placebo controlled trial comparing ipratropium with placebo in acute bronchitis. Subjects were referred by their primary care provider or from urgent care clinics at a single institution. Subjects had been diagnosed with acute bronchitis and had no significant co-morbidities.

INTERVENTION: Subjects received ipratropium or placebo inhalers, administering 2 puffs four times daily. A structured telephone interview took place 2, 4, and 8 days after enrollment. Medical records were reviewed at 60 days.

OUTCOME: The primary endpoint was improvement in cough symptomology; secondary endpoints included subsequent antibiotic prescriptions and “well being. ” RESULTS: The ipratropium arm improved significantly (better: 57. 6% day-2, 68. 3% day-4, 91. 9% day-8; c2 (1) = 21. 24, p < .01) across the 8 days of the telephone survey. This score improved over the same time period in the placebo arm, however the change was smaller and the difference was not significant (better: 64. 8% day-2, 74. 6% day-4, 79. 7% day-8; c2 (1) = 4. 69, p =.321). More than twice as many subjects in the placebo arm received subsequent antibiotic prescriptions compared to the ipratropium arm (12 vs. 5 respectively), this trend did not meet the threshold of significance (c2 (1) = 2. 84, p =.076).

CONCLUSION: Patients with acute bronchitis who are otherwise healthy have a more rapid improvement in their cough symptom score when they are treated with ipratropium, and may be at decreased risk of unnecessary antibiotic exposure.

Official title: Effect of Ipratropium on Acute Bronchitis in Subjects Without Underlying Lung Disease

Study design: Treatment, Randomized, Double-Blind, Placebo Control, Parallel Assignment, Efficacy Study

Primary outcome: Improvement in cough symptomology

Secondary outcome:

Subsequent antibiotic prescriptions

Frequency of follow up visits for similar complaints in the subsequent two months

Sense of well being

Time away from work or usual activities.

Detailed description: METHODS

COUGH STOP was an investigator-initiated study. We conducted a prospective, randomized, double blind, placebo controlled trial to test the hypothesis that ipratropium would improve cough symptoms in otherwise healthy subjects with acute bronchitis. Subjects were enrolled between October 9th 2002 and November 1 2003, and were included if they had a cough with or without sputum production for less than 30 days duration; were age 18 through 65; and were willing to follow up by phone for a brief interview at 2, 4, and 8 days after enrollment. Subjects were excluded if they had a history of COPD; asthma; or other lung disease; had localized lung findings on exam to suggest pneumonia or asthma; chest X-ray (if done) with evidence of pneumonia; purulent nasal discharge or other evidence of bacterial sinus infection; evidence of streptococcal pharyngitis; temperature greater than 101. 5 in the preceding 72 hours; treatment of a respiratory tract infection in the last 30 days; pregnancy; breast feeding; actively trying to become pregnant; history of heart failure; history of renal failure or insufficiency with a creatinine greater than 2. 0 mg/dl; history of psychiatric illness other than minor depression; currently incarcerated; or were unwilling to sign the consent form.

The study was reviewed and approved by the IRB for our facility, and approved by the FDA by way of an IND application. Subjects were either referred to one of the study investigators by a practicing physician or nurse practitioner at our facility, or were enrolled by a member of our team directly. Subjects were given a copy of the consent form, asked to review it and ask questions. Those who signed the consent form were randomly assigned to treatment with ipratropium or placebo metered dose inhaler (MDI). The assignment key was maintained by the pharmacy and by one of the investigators who had no interaction with the subjects or the data collection process. Subjects received training on how to use an MDI with a spacer device from a member of the study team. Subjects were instructed to take two puffs from the study MDI four times a day for the next 8 days. After the first 8 days they were instructed to use the study MDI on an as needed basis if they thought it was benefiting them.

During a structured enrollment interview subjects were asked the following questions: How long have you been coughing (number of days)? What other symptoms do you have? Are you producing sputum? Do you smoke? Are you coughing at night? If “Yes,” is it interrupting your sleep? Have you stopped working/daily activities? Are you having fevers? If “Yes,” how high are they? What over-the-counter medications are you using?

During the follow up telephone interviews, on days 2, 4, and 8 after enrollment, subjects were asked a similar but shorter set of questions: Are you still coughing? Is your cough better, worse, the same? Are you producing sputum? Is your sputum production better, worse, the same? Are you coughing at night? If “Yes,” is it interrupting your sleep? Have you returned to work/daily activities? Has your sense of well being returned? Are you having fevers? If “Yes,” how high are they? Are you having any side effects with the medication? If “Yes,” what are they? Are you having any problems using your inhaler? If “Yes,” please describe. What over-the-counter medications are you using? Subjects were not given any medical advice during the follow up interviews and were advised to address any medical questions with their primary care physician.

Medical records were reviewed after two months of enrollment for, frequency of return clinic visits, medication prescriptions, especially antibiotics, and complications related to study enrollment. Subjects who had either a subsequent antibiotic prescription or clinic visit for respiratory complaints in the 60 days following study enrollment had an audit of their medical records. Subjects who were prescribed antibiotics in this period had their records reviewed for the following: which antibiotic was prescribed; how long after enrollment it was prescribed; and why it was prescribed. This data was collected in a separate database and reviewed in a blinded fashion by the entire research team for inclusion in the final analysis. All decisions were unanimous, and based on the following factors: the diagnosis at the time of the prescription was consistent with that of an upper respiratory tract infection (URI); the antibiotic prescribed was consistent with treatment for URI; in cases where the diagnosis at the time of prescription could not be determined, the subject was included in the secondary analysis if the antibiotic prescribed was consistent with treatment of a URI. Subjects were excluded from the analysis if their diagnosis at the time of the prescription was not consistent with URI or if the antibiotic prescribed was not consistent with treatment of a URI.

Similarly, subjects who had clinic visits in the subsequent sixty-days had their records audited. Data was again collected in a separate database and reviewed in a blinded fashion by the entire team. Again, all decisions were unanimous, and criteria for inclusion were that the diagnosis at the time of the visit was consistent with that of a URI.

Statistical Analysis Power analysis indicated that a sample size of approximately 100 subjects in the treatment and control arms would be sufficient to detect a 33% reduction of cough frequency in the experimental arm receiving ipratropium, assuming a =.05 and b =.20, using a two– tailed z-statistic. Calculation of standard effect size for this power analysis was based upon extrapolation from Hueston’s and Melbye’s data13 15 on albuterol and fenoterol use in acute bronchitis, assuming a similar effect of ipratropium. Effect size for this calculation was based upon published values of relative risk in the references. Power analysis was not performed for other outcome variables.

Data was analyzed on an intention-to-treat basis, according to randomized assignment. The ipratropium and placebo arms were compared for: self-reported cough severity [same, better, worse]; cough duration [present, not present] for days 2, 4, 8; , well-being [well, not-well] for days 2, 4, 8; work absence [attended work, did not work] for days 2, 4, 8. Proportions and rates for non-continuous grouped variables were compared using chi–square test. Normally distributed continuous variables, such as cough duration, were compared between treatment arms using a two-tailed t-test.

RESULTS

A total of 151 subjects were referred to the study. Six subjects refused to participate at the time of referral and were excluded. One subject in the treatment arm voluntarily withdrew from the study and was excluded from analysis. One subject in the placebo arm met psychiatric exclusion criteria after audit of the medical record and was excluded from analysis. One subject in the treatment arm was found to meet exclusion criteria for fever after audit of the data and was excluded from analysis. Two subjects were lost to follow up and excluded from the analysis. The remaining 140 subjects (68 in the ipratropium arm, 72 in the placebo arm) were included in an intention to treat analysis (Figure 1). Baseline characteristics and demographics are listed in Table 1.

Cough symptoms

The ipratropium arm improved significantly (better: 57. 6% day-2, 68. 3% day-4, 91. 9% day-8; c2 (1) = 21. 24, p < .001) across the 8 days of the telephone survey. This score improved over the same time period in the placebo arm, however the change was smaller and the difference was not significant (better: 64. 8% day-2, 74. 6% day-4, 79. 7% day-8; c2 (1) = 4. 69, p =.321) (figure 2, table 3). The percentage change in the treatment arm was 34. 3% (57. 6% day-2, 91. 9% day-8) compared to 14. 9% over the same time period in the placebo arm (64. 8% day-2, 79. 7% day-8). Sputum production severity improved over the same time period in the treatment group, but the trend was not significant (better: 46. 9% day-2, 55. 6% day-4, 67. 4% day-8; c2 (1) = 5. 43, p =.246). There was no significant trend for sputum production severity in the placebo group (better: 64. 1% day-2, 75. 0% day-4, 65. 0% day-8, c2 (1) = 3. 70, p =.448) (Table 5).

Return to regular activities and return of “well being” In both the ipratropium and placebo arms the effect of time on returning to work or regular activities was significant (back to regular activities, ipratropium: 62. 1% day-2, 71. 4% day-4, 90. 3% day-8, c2 (2) = 13. 75, p = 0. 001; placebo: 57. 7% day-2, 70. 4% day-4, 97. 0% day-8, and c2 (2) = 29. 52, p £ .001) (Figure 3). Similarly the effect of time on return of the subjective measure of “well being” was significant in both the ipratropium and placebo arms, although less marked than with “back to regular activities” (“well being,” ipratropium: 30. 3% day-2, 47. 6% day-4, 63. 9% day-8, c2 (2) = 14. 42, p = .001; placebo: 29. 6% day-2, 53. 5% day-4, 67. 2% day-8, c2 (2) = 20. 09, p = .001) (Figure 4) Sixty percent of all subjects reported returning to regular activities on day 2 after enrollment. This increased to ninety four percent by day 8. Of subjects who described themselves as ‘not well’ on day 2-post diagnosis 14 percent reported going to regular activities, whereas on day 8-post diagnosis, 55 percent of subjects who described themselves as ‘not well’ reported returning to regular activities.

Antibiotic prescriptions

Twenty-three subjects received prescriptions for antibiotics either at time of enrollment or during 60 days post-enrollment. The referring provider prescribed two subjects antibiotics at the time of enrollment (one in the placebo arm, one in the ipratropium arm). This was allowed in the study protocol, however these subjects were excluded from the analysis of subsequent antibiotic prescriptions. The remaining 21 subjects underwent an audit of their medical records by the research team, which was blinded to their study assignment. Three subjects were excluded from the analysis because the diagnosis at the time of prescription was not consistent with AB. One subject was excluded because the antibiotic prescribed was not consistent with treatment for AB (acyclovir), leaving 17 subjects in the final analysis.

More than twice as many subjects in the placebo arm received subsequent antibiotic prescriptions for respiratory complaints compared to the ipratropium arm (12 vs. 5 respectively), however this trend did not meet the threshold of statistical significance (c2 (1) = 2. 84, p =.076).

Clinic Visits Twenty-eight subjects had clinic visits subsequent to enrollment with pulmonary related complaints, fourteen in the treatment arm and sixteen in the placebo arm (one subject was excluded from analysis because the diagnosis, tonsillectomy, was not consistent with URI). There was no significant difference between the ipratropium and placebo arms (c2 (1) = 1. 15, p £ 1. 0)

Overall subjects in both the placebo and the intervention arms had good outcomes. One subject in the ipratropium arm received a radiographically confirmed diagnosis of pneumonia 4 days after enrollment and was successfully treated with azithromycin as an outpatient. One subject in the placebo arm was given a diagnosis of pneumonia 13 days after study enrollment and was treated with azithromycin. The subject’s chest X-ray at the time of diagnosis, however, was interpreted as normal by a radiologist. Only one subject had multiple follow up visits with pulmonary complaints (“cough”) during the study period (days 24 and 32 post enrollment). None of the subjects required hospitalization or Emergency Department treatment during the study period.

Minimum age: 18 Years. Maximum age: 65 Years. Gender(s): Both.

Criteria:

Inclusion Criteria:

- cough with or without sputum production for less than 30 days duration; were age 18

through 65; and were willing to follow up by phone for a brief interview at 2, 4, and 8 days after enrollment

Exclusion Criteria:

- history of COPD; asthma; or other lung disease; had localized lung findings on exam to

suggest pneumonia or asthma; chest X-ray (if done) with evidence of pneumonia; purulent nasal discharge or other evidence of bacterial sinus infection; evidence of streptococcal pharyngitis; temperature greater than 101. 5 in the preceding 72 hours; treatment of a respiratory tract infection in the last 30 days; pregnancy; breast feeding; actively trying to become pregnant; history of heart failure; history of renal failure or insufficiency with a creatinine greater than 2. 0 mg/dl; history of psychiatric illness other than minor depression; currently incarcerated; or were unwilling to sign the consent form.

South Sacramento Kaiser Permanente, Sacramento, California 95823, United States

Starting date: October 2002
Ending date: January 2004
Last updated: August 31, 2006