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Norris SL, McNally TK, Thakurta S. Drug Class Review: Quick-relief Medications for Asthma: Final Report Update 1 [Internet]. Portland (OR): Oregon Health & Science University; 2008 Oct.

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Drug Class Review: Quick-relief Medications for Asthma: Final Report Update 1 [Internet].

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Literature Search

To identify relevant citations, 2 independent reviewers identified potentially relevant titles and abstracts from the Cochrane Central Register of Controlled Trials (Issue 1, 2006), Cochrane Database of Systematic Reviews, DARE, and MEDLINE (1966 to February, week 4, 2006). For Update 1 we searched these databases until June 2, 2008. Search terms included drug names and indications (see Appendix A for complete search strategies). To identify additional studies, we also searched reference lists of included studies and reviews and we reviewed dossiers submitted by pharmaceutical companies. All citations were imported into an electronic database (EndNote 9.0.0, Thomson Scientific).

Articles deemed potentially relevant after review of titles and abstracts were retrieved in full-text form. Two independent reviewers achieved consensus on all included and excluded articles. Excluded articles were coded in the EndNote database with the reason for exclusion.

Study Selection

We reviewed a selection of drugs currently available in the United States and of interest to the organizations participating in the Drug Effectiveness Review Project (Table 1). In addition, we were asked to review 2 drugs available only in Canada: terbutaline (Bricanyl™) and fenoterol (Berotec™).

Table 1

Table 1

Pharmacokinetics, indications and dosing of included drugs

We excluded studies that examined mixed populations where outcomes were not presented for subgroups of interest to us.

We examined studies that present 1 or more of the primary outcomes of interest to this review, effectiveness outcomes and outcomes related to safety and harms. For effectiveness and safety, published and as well as unpublished English-language reports in any geographic setting were included if they had a total sample size ≥ 10. We included letters if primary data were presented and there was sufficient detail to evaluate quality. We excluded abstracts and conference proceedings, as these publications generally do not have sufficient detail to assess internal or external validity. Theses were not included as the full-text is frequently difficult to retrieve.

For the assessment of efficacy and effectiveness we included reports of randomized controlled trials and controlled clinical trials that directly compared the drugs of interest to us (that is, head-to-head trials). For the assessment of adverse effects we examined studies with head-to-head comparisons only, but we included a broad range of study designs: observational studies, before-after studies, case series with a sample size ≥ 10, randomized controlled trials, and controlled clinical trials. Clinical trials often are not designed to assess adverse events, may select low-risk patients (in order to minimize drop-out rates), or may have too short a follow-up period in which to adequately assess safety. Observational studies designed to assess adverse event rates may include broader populations, carry out observations over a longer period, use higher quality methods for assessing adverse events, or examine larger sample sizes.

The important differences between the original report and this update with respect to scope are as follows:

  1. The original report focused only on beta2-agonists. This update includes short-acting anticholinergic drugs and the combination of short-acting beta2-agonist and short-acting anticholinergic agents.
  2. The original report included short-acting and long-acting beta2-agonists. This update includes only short-acting beta2-agonists, as it is focused on quick-relief medications for asthma.
  3. The original report included chronic obstructive pulmonary disease as well as asthma (including exercise-induced asthma); this update examined only asthma (including exercise-induced asthma).

The addition of short-acting anticholinergic drugs in Update 1 necessitated a completely new review of ipratropium bromide. We identified 2 recent high-quality Cochrane systematic reviews of anticholinergic therapy for chronic asthma in children over 2 years of age9 and in adults.12 We used these 2 reviews as the basis for our review of ipratropium bromide. These reviews focused on chronic asthma. The review in children included studies in which the anticholinergic agent was used for more than 1 week and the review in adults12 included only studies with follow-up of greater than 24 hours. The last search date for the review by McDonald and colleagues9 was February 2007 and for the review by Westby and colleagues,12 May 2004. We updated the searches, adding relevant studies of both acute and chronic asthma. Thus we did not examine the effectiveness or safety of ipratropium bromide in acute asthma in studies published prior to 2004.

Because the use of ipratropium bromide in exercise-induced bronchospasm was not reviewed in these 2 Cochrane reviews, we searched specifically for this drug-indication combination, with no restriction on search dates (see Appendix A).

Inclusion and exclusion criteria: Update 1

Included populations

  1. Adults or children with asthma including those with exercise-induced bronchospasm

Excluded populations

  1. Persons with chronic obstructive pulmonary disease
  2. Persons with acute bronchitis
  3. Persons with bronchiectasis
  4. Children less than 2 years old with recurrent or persistent wheezing
  5. Persons with cystic fibrosis
  6. Persons with high-altitude pulmonary edema

Included interventions

  1. Inhaled short-acting beta2-agonists
    1. Albuterol (salbutamol in Canada) metered dose inhaler and nebulizer solution
    2. Levalbuterol (that is, (R)-albuterol; not available in Canada) metered dose inhaler and nebulizer solution
    3. Pirbuterol (not available in Canada)
    4. Terbutaline: available only in Canada
    5. Fenoterol: available only in Canada
  2. Short-acting anticholinergics
    1. Ipratropium bromide metered dose inhaler and nebulizer solution
  3. Combination products
    1. Ipratropium bromide with albuterol metered dose inhaler (Combivent®) or ipratropium bromide with albuterol nebulizer solution

Excluded interventions

  1. Systemic corticosteroids
  2. Long-acting anticholinergics: tiotropium
  3. Studies in which bronchospasm was induced by methacholine, histamine, or cold
  4. Combination products that include a quick-relief agent and another agent not included in this review

Included comparisons

  1. Head-to-head studies examining the above bronchodilators

Excluded comparisons

  1. Comparisons to other drugs or to placebo (to achieve indirect comparisons)

Included effectiveness outcomes

  1. Symptoms such as cough, wheezing, shortness of breath
  2. Change in treatment regimen for the exacerbation
  3. Healthcare utilization (length of stay in the emergency department or other clinical facility, need for re-treatment within 24 hours, number of hospital admissions, length of hospital stay)
  4. For exercise-induced bronchospasm: exercise tolerance, symptoms
  5. Mortality

Included safety outcomes

  1. Overall adverse events
  2. Withdrawals due to adverse events
  3. Serious adverse events

Included settings

  1. Outpatient settings including urgent care facilities and the emergency department

Included study designs

  1. For effectiveness, head-to-head randomized controlled trials or controlled clinical trials with total sample size ≥ 20; No minimum duration of follow-up
  2. For adverse events, head-to-head randomized controlled trials, controlled clinical trials, or observational studies with sample size ≥ 10; no minimum duration of follow-up

Data Abstraction

We abstracted relevant descriptive and outcomes data into a relational database developed for this review. We recorded results of intention-to-treat analyses, when reported. If only per protocol results were reported, we specified the nature of these results and reported them. In trials with crossover, outcomes for the first intervention were recorded if available. Results of the first intervention would avoid the potential for bias due to differential withdrawal before crossover, a “carryover effect” (from the first treatment) in studies lacking a washout period, and a “rebound” effect from withdrawal of the first intervention.

Quality Assessment

We assessed the internal validity (quality) of controlled clinical trials using the predefined criteria listed in the quality assessment tool found in Appendix B. These criteria are based on those used by the United States Preventive Services Task Force and the National Health Service Centre for Reviews and Dissemination. For each included trial we assessed the following features: methods used for randomization, for allocation concealment, and for blinding of participants, investigators, and assessors of outcomes; the similarity of comparison groups at baseline; adequacy of reporting of attrition, crossover, adherence, and contamination; presence of post-allocation exclusions; and the use of intention-to-treat analysis.

We assessed observational and other study designs with adverse event data on the basis of unbiased selection of patients, attrition, unbiased and accurate ascertainment of events, and control for potential confounders (Appendix B).

These criteria were then used to categorize studies into good-, fair-, and poor-quality studies. Studies that had a significant flaw in design or implementation such that the results were potentially not valid were categorized as “poor”. Studies which met all quality criteria were rated good-quality; the remainder were rated fair. As the “fair-quality” category is broad, studies with this rating vary in their strengths and weaknesses. Studies rated poor are presented in the in-text tables and the evidence tables, and may be referenced in the text, but do not contribute to the conclusions of this report.

External validity of studies was assessed by examining the following: whether the study population was adequately described; inclusion and exclusion criteria; and whether the treatment received by the comparison group was reasonably representative of standard practice.

Systematic reviews that fulfilled inclusion criteria were rated for quality using predefined criteria (see Appendix B): clearly stated questions and inclusion criteria, adequate search strategy, quality assessment of individual trials, provision of adequate information, and appropriate methods of synthesis.

Data Analysis and Synthesis

For Update 1 we compared short-acting beta2-agonists, ipratropium bromide, and combinations of these 2 drugs/classes to each other. We did not include a review of the long-acting beta2-agonist formoterol because although it has a more rapid onset of action than salmeterol,1 it is not indicated as a rescue medication for asthma.1

Important descriptive information about population, setting, intervention, and quality of studies is presented in tables. Data were synthesized and are presented in a narrative, as there was too much clinical and methodologic diversity to pool the data in a meta-analysis.

Copyright © 2008, Oregon Health & Science University, Portland, Oregon.
Bookshelf ID: NBK47254
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