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Jonas DE, Wines RCM, DelMonte M, et al. Drug Class Review: Controller Medications for Asthma: Final Update 1 Report [Internet]. Portland (OR): Oregon Health & Science University; 2011 Apr.

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Drug Class Review: Controller Medications for Asthma: Final Update 1 Report [Internet].

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Introduction

Asthma is a chronic lung disease characterized by reversible airway obstruction, inflammation, and increased airway responsiveness. As a result of inflammation, individuals with asthma may experience symptoms such as wheezing, difficulty breathing, or coughing. The airway obstruction which occurs with asthma is generally reversible spontaneously or with treatment. Asthma is thought to have a genetic, inheritable component, often begins early in life, and consists of variable symptoms regardless of asthma classification. 1 The Expert Panel of the National Asthma Education and Prevention Program (NAEPP) recently reclassified asthma categories; the mild intermittent category was eliminated (now called intermittent) and the persistent category was subdivided into mild, moderate, or severe.1 The change was partly done to acknowledge that exacerbations can be severe in any asthma category. Table 1 lists the criteria used to classify asthma severity.

Table 1. Classification of asthma.

Table 1

Classification of asthma.

Asthma outcomes have improved over the past several years but the burden remains substantial. Asthma is estimated to affect 300 million individuals worldwide with 22 million of those individuals being in the US.2–4 It is the cause of 250,000 worldwide deaths annually with 4,000 of them in the US.2–4 The World Health Organization estimates 15 million disability-adjusted life years (DALYs) lost annually due to asthma.2 Based on 2007 data, asthma accounts for 19.7 billion dollars annually in the US with 14.7 billion in direct, 5 billion in indirect, and 6.2 billion in prescription cost. In 2005, there were 488,594 hospital discharges in the US, 12.8 physician office visits, 1.3 million hospital outpatient department visits, and 1.8 million emergency department visits due to asthma in the United States.4

Many current medications available to treat persistent asthma target the inflammatory process caused by multiple inflammatory cells and mediators including lymphocytes, mast cells, eosinophils, among others.1 There are currently two categories of medications used in asthma treatment: controller medications and quick relief (or rescue) medications. Although all patients with persistent asthma should have a short-acting relief medication on hand for treatment of exacerbations and a controller medication for long-term control, this report will focus on the following currently available controller medications: inhaled corticosteroids (ICSs), Long-Acting Beta-2 Agonists (LABAs), leukotriene modifiers, anti-IgE medications, and combination products.

Inhaled corticosteroids are the preferred agents for long-term control of persistent asthma according to expert panel recommendations.1 The inhaled route of administration serves to directly target the inflammation while minimizing systemic effects which can result from oral administration. These agents act via anti-inflammatory mechanisms and have been approved as first line therapy for asthma control in all stages of persistent asthma.1 The 7 ICSs currently available include: beclomethasone dipropionate, budesonide, ciclesonide, flunisolide, fluticasone propionate, mometasone furoate, and triamcinolone acetonide. Table 2 lists the trade names, manufacturers, available formulations, and age indications for controller medications for persistent asthma. Although it is not approved for the treatment of asthma and thus is not included in Table 2, tiotropium (Spiriva®) was included in this report to determine if there is any published evidence for its use in people with asthma. Dulera (mometasone/formoterol), now approved for treatment of asthma in people ≥12 years, is not included in this report because it was approved after our cutoff date for the inclusion of new medications.

Table 2. Long-term controller medication class, trade names, manufacturers, formulations, and indications.

Table 2

Long-term controller medication class, trade names, manufacturers, formulations, and indications.

Inhaled corticosteroids are delivered through a variety of devices including metered dose inhalers (MDIs), dry powder inhalers (DPIs), or nebulizers. In the past, MDI products contained chlorofluorocarbons (CFCs) which were found to be detrimental to the ozone and have now been banned from use. They were replaced with alternative administration devices including hydrofluoroalkane propellant (HFA) MDIs and dry powder inhalers. The ICSs often have different kinetic and side effect profiles with similar numerical doses depending on the delivery device and the product.1 Since there are not enough head-to-head trials comparing all of the various ICSs, determining equivalency among products is sometimes difficult. Table 3 lists comparative dosing of the available products based on the recently updated NAEPP guidelines.1

Table 3. Estimated comparative daily dosages for inhaled corticosteroids.

Table 3

Estimated comparative daily dosages for inhaled corticosteroids.

Long-Acting Beta-2 Agonists (LABAs) are agents used in combination with ICSs to obtain control in persistent asthma. The mechanism of action of these agents is through relaxation of airway smooth muscles to reverse bronchoconstriction.1, 5 In contrast to short -acting beta-2 agonists, which are used for quick relief of acute symptoms due to their quick onset and short-duration of action, LABAs provide long-acting bronchodilation for 12 hours allowing for twice daily administration.1 The NAEPP expert panel advocates the use of LABAs as the preferred adjunct therapy with ICSs in individuals ≥ 12 years old for persistent asthma.1 In addition, LABAs are useful in the prevention of exercise-induced bronchospasm (EIB).1, 5 These agents are not recommended nor approved for relief of acute asthma symptoms or for use as monotherapy for persistent asthma.1 Currently there are two available LABAs: formoterol (formerly known as eformoterol in the UK) and salmeterol. Arformoterol is available in the US but is currently approved only for COPD (Table 2). The main clinical difference in the two available agents is that formoterol has a quicker onset of action than salmeterol.1

The leukotriene modifiers are another class of controller medications used in the treatment of asthma and are comprised of two classes of medications: leukotriene receptor antagonists (montelukast and zafirlukast) and 5-lipoxygenase inhibitors (zileuton) (Table 2). Leukotrienes cause contraction of smooth muscles, mucous secretion, and inflammation contributing to asthma symptoms.1, 5 The leukotriene receptor antagonists (LTRAs) bind to cell receptors to prevent these actions from occurring.1 Montelukast is approved for children ≥ 1 year old and zafirlukast for children ≥ 5 years old in the United States and ≥ 12 years old in Canada. They are approved for mild persistent asthma and as adjunct therapy with ICSs.1, 5 Montelukast is also approved for EIB.5 The leukotriene modifiers are the only medications delivered orally in pill-form, rather than as inhalers, for the treatment of persistent asthma.

Zileuton’s mechanism of action is through the inhibition of 5-lipoxygenase which is involved in the production of leukotrienes.1 This medication is indicated for use in children ≥ 12 years old.1, 5 Metabolism of this drug is through the CYP 450 1A2, 2C9, and 3A4 isoenzymes which are responsible for a variety of drug-drug interactions.5 In addition, liver function monitoring is required with zileuton therapy,1, 5 due to the involvement of the CYP 450 system and potential adverse events, which has limited the use of this product.

The newest class of asthma control medications is the anti-IgE medication class, which currently consist of one agent, omalizumab (Table 2). This agent binds to IgE receptors on mast cells and basophils to decrease sputum production and asthma symptoms.1 Omalizumab is approved for use in patients ≥ 12 years old who have uncontrolled asthma on inhaled corticosteroids.1, 5 This agent is an injectable medication (given every two to four weeks) approved for adjunct therapy with ICSs in moderate to severe persistent asthma as well as for adjunct therapy with high dose ICSs plus LABA in severe persistent asthma.1

Lastly, the combination controller medications available for the treatment of asthma include fluticasone/salmeterol (FP/SM) and budesonide/formoterol (BUD/FM) (Table 2). These medications are both combinations of an ICS and a LABA and are indicated for use in those patients requiring two agents for control.1, 5 These combination products can be used when monotherapy with ICS is not adequate or when disease severity warrants treatment with two controller medications. These agents are available as DPI or HFA products (Table 2).

Purpose and Limitations of Evidence Reports

Systematic reviews, or evidence reports, are the building blocks underlying evidence-based practice. An evidence report focuses attention on the strength and limits of evidence from published studies about the effectiveness of a clinical intervention. The development of an evidence report begins with a careful formulation of the problem. The goal is to select questions that are important to patients and clinicians, then to examine how well the scientific literature answers those questions. Terms commonly used, such as statistical terms, are provided in Appendix A and are defined as they apply to reports produced by the Drug Effectiveness Review Project. Topic-specific abbreviations used in this report are presented in Appendix B.

An evidence report emphasizes the patient’s perspective in the choice of outcome measures. Studies that measure health outcomes (events or conditions that the patient can feel, such as quality of life, functional status, and fractures) are emphasized over studies of intermediate outcomes (such as changes in bone density). Such a report also emphasizes measures that are easily interpretedin a clinical context. Specifically, measures of absolute risk or the probability of disease are preferred to measures such as relative risk. The difference in absolute risk between interventions is dependent on the numbers of events in both groups, such that the difference (absolute risk reduction) is smaller when there are fewer events. In contrast, the difference in relative risk is fairly constant across groups with different baseline risk for the event, such that the difference (relative risk reduction) is similar across these groups. Relative risk reduction is often more impressive than the absolute risk reduction. Another measure useful in applying the results of a study is the number needed to treat (or harm), the NNT (or NNH). The NNT represents the number of patients who would have to be treated with an intervention for 1 additional patient to benefit (experience a positive outcome or avoid a negative outcome). The absolute risk reduction is used to calculate the NNT.

An evidence report also emphasizes the quality of the evidence, giving more weight to studies that meet high methodological standards that reduce the likelihood of biased results. In general, for questions about the relative benefits of a drug, the results of well-done, randomized controlled trials are regarded as better evidence than results of cohort, case-control, or cross-sectional studies. In turn, these studies are considered better evidence than uncontrolled trials or case series. For questions about tolerability and harms, controlled trials typically provide limited information. For these questions, observational study designs may provide important information that is not available from trials. Within this hierarchy, cohort designs are preferred when well conducted and assessing a relatively common outcome. Case control studies are preferred only when the outcome measure is rare, and the study is well conducted.

An evidence report pays particular attention to the generalizability of efficacy studies performed in controlled or academic settings. Efficacy studies provide the best information about how a drug performs in a controlled setting that allows for better control over potential confounding factors and bias. However, the results of efficacy studies are not always applicable to many, or to most patients seen in everyday practice. This is because most efficacy studies use strict eligibility criteria that may exclude patients based on their age, sex, medication compliance, or severity of illness. For many drug classes, including antipsychotics, unstable or severely impaired patients are often excluded from trials. Often, efficacy studies also exclude patients who have comorbid diseases, meaning diseases other than the one under study. Efficacy studies may also use dosing regimens and follow-up protocols that may be impractical in other practice settings. They often restrict options, such as combining therapies or switching drugs that are of value in actual practice. They often examine the short-term effects of drugs that in practice are used for much longer periods of time. Finally, efficacy studies tend to use objective measures of effects that do not capture all of the benefits and harms of a drug or do not reflect the outcomes that are most important to patients and their families.

An evidence report also highlights studies that reflect actual clinical effectiveness in unselected patients and community practice settings. Effectiveness studies conducted in primary care or office-based settings use less stringent eligibility criteria, assess health outcomes, and have longer follow-up periods than most efficacy studies. The results of effectiveness studies are more applicable to the “average” patient than results from highly selected populations in efficacy studies. Examples of effectiveness outcomes include quality of life, hospitalizations, and the ability to work or function in social activities. These outcomes are more important to patients, family, and care providers than surrogate or intermediate measures such as scores based on psychometric scales.

Efficacy and effectiveness studies overlap. For example, a study might use very narrow inclusion criteria like an efficacy study, but, like an effectiveness study, might examine flexible dosing regimens, have a long follow-up period, and measure quality of life and functional outcomes. For this report we sought evidence about outcomes that are important to patients and would normally be considered appropriate for an effectiveness study. However, many of the studies that reported these outcomes were short-term and used strict inclusion criteria to select eligible patients. For these reasons, it is neither possible nor desirable to exclude evidence based on these characteristics. Labeling each study as an efficacy or effectiveness study, while convenient, is of limited value; it is more useful to consider whether the patient population, interventions, time frame, and outcomes are relevant to one’s practice, or, in the clinical setting, how relevant they are to a particular patient.

Studies across the continuum from efficacy to effectiveness can be useful in comparing the clinical value of different drugs. Effectiveness studies are more applicable to practice, but efficacy studies are a useful scientific standard to determine whether the characteristics of different drugs are related to their effects on disease. An evidence report reviews the efficacy data thoroughly to ensure that decision-makers can assess the scope, quality, and relevance of the available data. This thoroughness is not intended to obscure the fact that efficacy data, no matter how much there is of it, may have limited applicability to practice. Clinicians can judge the relevance of the study results to their practice and should note where there are gaps in the available scientific information.

Unfortunately, for many drugs, there are few or no effectiveness studies and many efficacy studies. As a result, clinicians must make decisions about treatment for many patients who would not have been included in controlled trials and for whom the effectiveness and tolerability of the different drugs are uncertain. An evidence report indicates whether or not there is evidence that drugs differ in their effects in various subgroups of patients, but it does not attempt to set a standard for how results of controlled trials should be applied to patients who would not have been eligible for them. With or without an evidence report, these are decisions that must be informed by clinical judgment.

In the context of developing recommendations for practice, evidence reports are useful because they define the strengths and limits of the evidence, clarifying whether assertions about the value of the intervention are based on strong evidence from clinical studies. By themselves, they do not tell you what to do. Judgment, reasoning, and applying one’s values under conditions of uncertainty must also play a role in decision making. Users of an evidence report must also keep in mind that not proven does not mean proven not; that is, if the evidence supporting an assertion is insufficient, it does not mean the assertion is not true. The quality of the evidence on effectiveness is a key component, but not the only component, in making decisions about clinical policies. Additional criteria include acceptability to physicians or patients, the potential for unrecognized harms, the applicability of the evidence to practice, and consideration of equity and justice.

Scope and Key Questions

The purpose of this review is to assist healthcare providers, researchers and policy makers in making clinical decisions, creating formularies, and developing policies regarding long-term asthma control medications based on the most current available literature. We compare the efficacy, effectiveness, and tolerability of controller medications used in the treatment of persistent asthma as well as look for subgroups that may differ in these areas. The Research Triangle Institute International-University of North Carolina Evidence-based Practice Center (RTI-UNC EPC) wrote preliminary key questions, identifying the populations, interventions, and outcomes of interest, and based on these, the eligibility criteria for studies. These were reviewed and revised by representatives of organizations participating in the Drug Effectiveness Review Project (DERP) along with the RTI-UNC EPC, after considering comments received from the public which derived from a draft version posted to the DERP web site. The participating organizations of DERP are responsible for ensuring that the scope of the review reflects the populations, drugs, and outcome measures of interest to both clinicians and patients. The participating organizations approved the following key questions to guide this review:

  1. What is the comparative efficacy and effectiveness of controller medications used to treat outpatients with persistent asthma?
  2. What is the comparative tolerability and frequency of adverse events for controller medications used to treat outpatients with persistent asthma?
  3. Are there subgroups of these patients based on demographics (age, racial groups, gender), asthma severity, comorbidities (drug-disease interactions, including obesity), other medications (drug-drug interactions), smoking status, genetics, or pregnancy for which asthma controller medications differ in efficacy, effectiveness, or frequency of adverse events?

Inclusion Criteria

This review includes pediatric or adult outpatients with persistent asthma being treated with any of the following agents: inhaled corticosteroids (beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone propionate, triamcinolone, mometasone), Long-Acting Beta-2 Agonists (formoterol, arformoterol, salmeterol), leukotriene modifiers (montelukast, zafirlukast, zileuton), anti-IgE therapy (omalizumab), combination products (fluticasone propionate/salmeterol xinafoate, budesonide/formoterol), or tiotropium. For efficacy and effectiveness outcomes of interest we included randomized controlled trials of at least 6 weeks duration and a sample size of at least 40 which evaluate control of symptoms, functional capacity and quality of life, urgent care services, adherence, hospitalization, or mortality. For adverse events outcomes, we also included observational studies of at least 6 months duration and a sample size of at least 100 (Table 4). Further details related to inclusion criteria are provided below in the Methods section under Study Selection. Boxed warnings associated with these products are provided in Appendix C. Dosing equivalency of the agents was based on the 2007 NAEPP Expert Panel publication.1 A comparison of labeled and delivered doses for inhalers is provided in Appendix D.

Table 4. Outcome measures and study eligibility criteria.

Table 4

Outcome measures and study eligibility criteria.

Copyright © 2011 by Oregon Health & Science University.
Bookshelf ID: NBK56685

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