I am going to deal with asthma guidelines and effective utilization of long-acting beta2-agonists (LABAs).

In this program, we are going to talk about asthma severity; how one determines severity and applies the asthma clinical guidelines to the treatment; spend a significant amount of time dealing with the safety of LABAs; talk about some of the mechanisms for things to worry about with beta-agonists; and provide you with some guidance.

One of the things that I think is important when we talk about asthma is to understand that asthma, fundamentally, is an inflammatory disease. It is genetically predisposed; environmental factors -- such as viral illnesses, allergens, and prematurity -- are related to developing asthma. Remember, asthma is a reversible airway obstruction to the bronchial tube, but there is an inflammatory process that is present; once you have the inflammation, then you develop symptoms. It is genetic, environmental, and it has inflammation symptoms; it is not just symptoms. The end result of the asthma process is the symptoms -- cough, wheeze, shortness of breath, and chest tightness.

Let's talk about demographics. Many people do not realize the enormity of the problem. About 7.5% of the people in the United States have asthma at one point; that's 22 million people. Two thirds of them are adults, one third are children. But the majority of asthma starts in childhood: 80% of people with asthma begin in childhood, with first symptoms actually under the age of 5. We divide asthma by severity: mild intermittent, mild persistent, moderate persistent, severe persistent. We will talk about that. In the primary care arena, almost 25% of people with asthma have mild persistent disease. That is what you will see a lot of; you will see either mild persistent or mild intermittent. About one quarter of your patients have mild persistent asthma.

When you look at ethnic differences, African Americans have much more asthma: almost 10% prevalence, compared with Caucasians, which are at about 7.5%. In adults, more women than children and more women than men have asthma. In childhood, it is reversed: more males than females have asthma. Not many people die from asthma. It is not a very common disease that causes death, but it does cause significant morbidity.

When you are assessing severity, it is very important to not just identify that the patient has asthma, but you need to have a treatment plan. You cannot design a treatment plan without assessing severity, and also what control you want to accomplish. I am not going to be talking about environmental control -- getting rid of cigarette smoke, indoor allergens, allergens in the workplace or school or daycare -- and I am not talking about allergy injections. I am really going to concentrate, predominantly, on pharmacologic agents; but you need to assess severity and then decide how to treat.

How is severity determined? Asthma is a variable disease. It is not something that stays static; so over time, you are really reassessing severity. Severity depends on both objective measures, such as peak flow and spirometry, and its subjective measures, such as morning and nighttime symptoms, cough, wheeze, shortness of breath, chest tightness, sleep interference, worsening of symptoms, and how often one takes what we call a "rescue" or short-acting beta-agonist medication. When you assess the severity, it is important to do objective measures, and spirometry is the best. Also, ask the patients about symptoms and use of medications.

Another easy way of measuring severity is the Rules of Two, which is something that has been around a long time, but it works. In other words, in intermittent asthma, the symptoms or the treatment is less than twice a week, less than twice a month at night. The persistent patient has symptoms more than twice a week, more than twice a night per month, but not daily; that is mild persistence. The patient who has symptoms every day has moderate disease; the more severe patient has more severe continual symptoms.

Once you establish severity, then you must evaluate the patient and design a treatment plan at every visit. You need to define control based on continual reassessment of severity. When you see a patient, you want to know not only the things we talked about -- in terms of sleep disturbance, activity effect, lung function, use of beta-agonists -- but you also want to make sure that you know about associated triggers. A child starts a new school, the new workplace, there is a new place to live, there is water damage to the house, there is a new pet. Just make sure that there is no change within the environment that could be a trigger. Also, you want to know about the patient's being happy. If patients are not happy, if parents are not happy, the patient is not going to be happy with you, and then you are not going to be successful. So you are constantly evaluating the patients in this disease; how it interferes with their life.

It is important to establish realistic expectations. After you have explained that, every patient who has asthma needs to understand that it is a chronic disease. It is a variable disease; it is an inflammatory disease. The symptoms, again, are the end result of the inflammation that occurs in the airways. Then, you need to explain to patients how medicines work. Why are you doing what you are doing? What is the benefit of inhaled corticosteroids? What is the risk? Why should it be done? You also have to be able to explain to patients about compliance. I prefer the word "adherence"; meaning that you deal with the patient and/or the family. They make decisions with you, so they are part of the decision-making process. It is also important, as you take care of patients, that they should understand how to do things; how to use devices, how to use inhalers. Show them how to do it, then have them show you how to do it. Every time they come in, they should bring their devices with them.

The most crucial concept is the patient-family/patient-physician relationship, achieving control together as a partnership. You always should have a written asthma action plan. Most children over age 8, and obviously, hopefully, all adults can write their action plan. They write it in their own handwriting; you agree on it. You figure out how often the patient should be seen, depending on asthma severity. Again, we talk about satisfaction. Probe for compliance and adherence; and always, the patient should be happy. The patient should have some feeling of ownership in the management of their disease, so you are partners. Teamwork: it should be a team approach, not a doctor telling a patient; a team and an agreement among the whole team.

The goals of care? Very simple: you do not want to have symptoms; you do not want to have exacerbations. You want normal activity, normal school or work; no one will miss work or school. You do not want to go to the Emergency Department; you definitely do not want to be hospitalized. You want to create normality to the pulmonary function. Most importantly, you want to have minimal use of rescue medicine; you do not want to make patients sick from their treatment. These goals should be established; they should be agreed upon and written.

I am on the National Asthma Education and Prevention Program (NAEPP) guideline committee at the National Heart, Lung, and Blood Institute (NHLBI), and we had a lot of trouble figuring out how to present the medicines. What we came up with is very simple: long-term control medicine or quick-relief medicines. The long-term control medicines -- the one that is taken that controls symptoms either chronically, or at least for more than a few hours -- are the anti-inflammatory medications: corticosteroids, cromolyn (Intal) or nedocromil (Tilade), and leukotriene modifiers. And you have the bronchodilators: the LABAs and the theophylline medicines. Quick-relief medications: short-acting beta2-agonists; anticholinergic agents, which are not a very effective medicine for asthma; and a short course of systemic steroids. Those are the quick-relief medications.

When we talk about the use of medications, we define severity. So a patient with intermittent disease is on a short-acting beta2-agonist on an as-needed (prn) basis. Sometimes patients have exacerbations; they may need to be on systemic steroids, a nebulizer, or infrequently an inhaled beta2-agonist; but very infrequently. Their symptoms are not persistent; they do not have inflammation on a chronic basis.

Persistent patients -- they have inflammation all the time. The best anti-inflammatory medicine is inhaled corticosteroids. The mild patient gets a low dose; the moderate patient gets low- or medium-dose inhaled corticosteroids and a LABA. Severe patients get high-dose inhaled corticosteroids and LABAs. These are the recommendations from the NHLBI guidelines, based on asthma severity.

However, there is alternate treatment. In other words, it is not the preferred treatment, but there is ample evidence that the alternative treatment, in some cases, can be just as effective with less medication. So the mild patient can be on cromolyn or a leukotriene modifier. The moderate patient can be on monotherapy; can be on an inhaled corticosteroid by itself. He or she does not need a LABA, or a theophylline medicine, or a leukotriene modifier. Or, he could be on a low-dose inhaled corticosteroid, or a medium dose, with a leukotriene modifier or theophylline without getting a LABA. So there are more options in the mild or moderate persistent asthmatic. You are customizing therapy to each patient's needs, and these are the options recommended in the asthma treatment guidelines.

It is important to realize that inhaled corticosteroids are the most effective agents for long-term control of persistent asthma. Through the appropriate use of spacers, rinsing the mouth, or using a low dose, one can minimize the side effects. It is important that the patient and you understand that the most effective medicine for controlling symptoms in asthma is an inhaled corticosteroid.

I want to go through some studies looking at the role of inhaled corticosteroids and LABAs. In the Oxis (formoterol) and Pulmicort (budesonide) Turbuhaler in the Management of Asthma (OPTIMA) study, there were 2 groups of patients. Group A patients were not on an inhaled corticosteroid before they went into the study; these are patients with mild persistent asthma. The concept here was to see the effect of combining a low-dose inhaled corticosteroid with a low-dose LABA in patients with mild disease. So group A patients were corticosteroid-free at baseline. They were given either budesonide, which is an inhaled corticosteroid, by itself, 200 mcg a day; or budesonide 200 mcg a day plus low-dose formoterol, which is a LABA; or a placebo control. The patients were treated for 1 year. Approximately 2000 patients aged 12 years or older were in the study; a double-blind, randomized treatment study. Group A had about 700 patients. The main outcome was the time tosevere asthma exacerbation, defined as needing all steroids, hospitalization, or Emergency Department treatment, or a decrease in peak flow over a 2-day period.

This is how patients in group A fared. You can see along the y-axis, the rate per year of severe exacerbations for the 3 treatments. Budesonide alone reduced the risk of severe exacerbations by 60%; the addition of formoterol increased lung function. The data are not there, but there was no change in the endpoint. In this case, there was no difference in mild persistent asthma -- steroid-free to begin with -- between monotherapy with an inhaled corticosteroid and an inhaled corticosteroid plus a LABA.

Group B: these were 1200-plus patients who were on inhaled corticosteroids with mild persistent asthma when they entered the study. They received, in this case in addition to their treatment, 200 mcg of budesonide a day; 200 mcg of budesonide a day plus low-dose formoterol; or 400 mcg of budesonide a day with or without formoterol. These patients again were treated for 1 year.

In this group, adding formoterol reduced the risk for the first severe exacerbation, and also for poorly controlled days by 43% and 30%, respectively. In patients receiving inhaled corticosteroids before they started, adding formoterol was more effective than doubling the dose of corticosteroids. Looking at the right side of the graph, formoterol plus 400 mcg (200 mcg bid) of budesonide a day was more effective than 400 mcg (200 mcg bid) of budesonide a day alone. In this study, the inhaled corticosteroid patient group did better when one added formoterol. The patients who got monotherapy did not do so badly either, but with the formoterol addition, they did better.

What does the evidence say about mild persistent asthma? If you look at the NAEPP guidelines (those are US guidelines), or the Global Initiative for Asthma (GINA) guidelines, or the Cochrane analysis, you can see that -- for the treatment of mild persistent asthma, per the findings in multiple publications -- monotherapy with inhaled corticosteroids is the preferred treatment. These are mild persistent asthmatics; I showed the previous slides dealing with those patients in the study. The Cochrane analysis looking at the systemic review of randomized, clinical, controlled trials, demonstrated that monotherapy was the preferred treatment for mild persistent asthma, consistent with the guidelines.

Let's talk about achieving control with high-dose inhaled corticosteroids and LABAs. This was the Gaining Optimal Asthma Control (GOAL) study. It is a 1-year, randomized, stratified, double-blind, parallel-group study, no control, no placebo. About 3500 patients were randomized, in a 4-week run-in, to 1 of 3 treatments. After their disease was determined by severity (by their using beclomethasone), they were randomized to either fluticasone (Flovent) by itself or fluticasone plus a LABA; in this case, it was salmeterol. The way this study was done is that the patients were treated based on guidelines, and the goal of the analysis was total control, no symptoms; well controlled, symptoms, but very mild symptoms; and no control.

A very complicated study to go through; but the key finding was that for well-controlled patients (mild symptoms mostly during the day), the exacerbation rate and the improvement in health status were better with the salmeterol/fluticasone combination than with fluticasone by itself, no matter what the severity of disease when they went into the study. You can see the severity by looking at the x-axis; these are patients who were on 500 mcg of beclomethasone or more than 500 mcg (up to 1000 mcg) before they went into the study. But if you also look at it another way, patients who were treated just with fluticasone did pretty well, but they did better when they were on the combination therapy.

Another study was the Formoterol and Corticosteroids Establishing Therapy (FACET) study. This was a study looking at formoterol and budesonide in moderate persistent asthma. In this case, these were patients who were treated with either 200 mcg a day of budesonide, 200 mcg of budesonide plus formoterol, or 800 mcg of budesonide with or without formoterol. In this case, they looked at asthma's severe exacerbations; it was a 1-year study. Severity of exacerbations was defined, as before, as needing oral steroids or a 30% drop in peak flow over 2 consecutive days. The bottom line in this study was that in the patients with persistent asthma, despite the use of inhaled corticosteroids, the addition of formoterol to budesonide, or the use of higher-dose budesonide was beneficial. There was no difference between using high-dose, in this case, budesonide, and adding formoterol. The number of exacerbations was no different. So in this case, the addition of a LABA, in terms of the primaryoutcome, did not make a difference.

All that we have talked about, basically, is that mild persistent asthma can be treated with monotherapy. The addition of LABAs was not beneficial. In moderate persistent asthma, depending on how you do the study, either the GOAL study or the FACET study, the combination of a LABA and inhaled corticosteroid is better than an inhaled corticosteroid in some cases. In other cases, using mild therapy inhaled corticosteroids in the moderate persistent asthma can be very effective without a long-acting bronchodilator. And this gets to the gist of why we want to worry about this.

The question is: are beta2-agonists safe? It is the most commonly used medicine; the best medicine, for either relieving symptoms or preventing exercise asthma. But there is a suggestion and a big controversy about whether there is increased mortality, increased asthma exacerbations, or worse asthma control using beta2-agonists. Let's look at this issue in detail.

The US Food and Drug Administration (FDA) in November of 2005 issued a Public Health Advisory basically saying that there is an increase of severe asthma exacerbation or possibly death with the regular use of a LABA. Specifically, the advisory affects salmeterol (Serevent Diskus) alone or with fluticasone (Advair Diskus). The advisory was based on a July 2005 meeting of the FDA reviewing the Salmeterol Multicenter Asthma Research Trial (SMART). I will talk about SMART in a few seconds.

I would like to draw your attention to the FDA advisory recommendations. I would like to read these to you, because this is important. The recommendation is that LABAs should not be the first medicine used to treat asthma. The LABAs should be added to the asthma treatment plan only if other medications do not control asthma, including the use of low- or medium-dose corticosteroids. Do not use LABAs to treat wheezing that is getting worse. Patients should know to call you if that happens. The LABAs are not relief medicines; they do not relieve wheezing. Patients are recommended not to stop LABAs or other asthma medicines without discussing this with their doctor.

The FDA made the manufacturers of LABAs (GlaxoSmithKline for fluticasone propionate/salmeterol xinafoate [Advair] and salmeterol xinafoate [Serevent], and Novartis and Schering for formoterol fumarate [Foradil]) have their labeling include the summary of the SMART study, which showed an increase in asthma-related deaths in patients with salmeterol over a 7-month period.

What are the practical implications of the FDA Public Health Advisory? The implications are that for a patient with moderate persistent asthma or mild persistent asthma, long-term control is key, for which the preferred regimen is monotherapy with inhaled corticosteroids. If control cannot be achieved with an inhaled corticosteroid, the practitioner should consider adding a LABA; a LABA should not be prescribed as primary treatment -- very important.

Let's talk about some of the background to this. In 1993, when salmeterol was released in the United Kingdom, there was a Serevent Nationwide Surveillance (SNS) study. This was a double-blind, randomized clinical trial for 16 weeks. It was done in a general practice setting with approximately 25,000 patients over 12 years. These patients were given regular treatment with salmeterol vs albuterol in a 2:1 ratio; salmeterol 50 mcg twice a day vs albuterol 2 puffs 4 times a day. The main outcome was serious events and withdrawals, whether or not they were considered to be related to drugs. It was a 16-week trial.

The results were that there was no statistical difference, other than asthma-related withdrawal. There were more withdrawals with the albuterol treatment vs the salmeterol treatment. But looking at asthma-related deaths (the second line), there was a numerical increase in deaths in the salmeterol group, and 3 times the relative risk, which was not statistically significant. So there were significantly fewer withdrawals with salmeterol, but the frequency of asthma-related death, although low in both groups, was numerically, but not significantly, higher in the salmeterol group.

Because this study suggested that salmeterol may increase the risk of asthma death, the FDA in the United States initiated the SMART study. This was a 7-month, multicenter, randomized, double-blind, parallel, placebo-controlled, observational surveillance study. There were 50,000 patients who were supposed to be in the study; but after half the patients were in the study, the data were evaluated. In this group, the patients had their regular care; then half of the group took salmeterol twice a day, 42 mcg, and the other half took placebo plus their usual care. The main outcome was combined respiratory-related death or respiratory-related life-threatening experience -- intubation, or mechanical intubation and canula ventilation that was defined as life-threatening.

These are the SMART study results. The key point in this is the occurrence of the primary outcome -- respiratory-related death: life-threatening experience was low and not significantly different for salmeterol or for placebo. If you look at relative risk, there was a 1.4-fold increased risk of respiratory death or life-threatening experience in patients who took salmeterol vs placebo. The increase is greater, but not necessarily just in African American patients. There was also a small significant increase in respiratory-related deaths and asthma-related deaths in subjects on salmeterol, although the imbalance occurred largely, but not entirely, in the African American population. There was a 4-fold risk of asthma-related respiratory death or life-threatening death in the African American group.

What are the key findings, and what is the issue? More events occurred in patients receiving salmeterol. Although African American patients had a higher asthma-related death rate than Caucasians, subgroup analysis revealed that the relative risk was similar in both groups. The problem with the study, and the problem with the SNS study, is that it did not provide data on the effect of, or the potential to test, the protective effect of inhaled corticosteroids, because they did not really look for that. But post hoc analysis did show that inhaled corticosteroids did not provide a protective effect in terms of patients on LABAs or those on placebo.

What does this all mean, and what is the explanation? Let's talk about some of the other studies that relate to this issue. Why do some patients have adverse events or effects when using inhaled beta-agonists? There is worsening air flow, and poor clinical outcome. Why do some patients have problems, others do not? Part of the answer may be found in our genes. There are polymorphisms of the beta-adrenergic receptor. There is a glycine/glycine polymorphism; this is predominantly in position 6. There are glycine/glycine, glycine/arginine, and arginine/arginine homozygous patients. There is a suggestion that the arginine/arginine polymorphism may be a risk factor in regard to beta-agonists.

One study that attempted to address the question about genetics and response to asthma medicine is the Beta-Agonist Response by Genotype (BARGE) study. It was a prospective, randomized, placebo-controlled, double-blind trial using 2 puffs of albuterol 4 times a day vs pure "nonuse" in patients with arginine/arginine and glycine/glycine genotype. These were adults; steroid-naive patients. It was single-blind in the 6-week run-in, crossover design, so the patients were their own control; there was an 8-week washout between treatment weeks.

The primary outcome was to change their morning peak flow. Whether you look at morning peak flow, nighttime peak flow, or morning symptoms, patients with the arginine/arginine genotype did worse than did patients with the glycine/glycine. So it was something about the arginine/arginine genotype that made patients worse than patients who were glycine/glycine. Remember, the patients were their own control.

For the patients with arginine/arginine, actually, their asthma and control improved during the time that they had stopped the beta-agonist. The patients with glycine/glycine did the same with or without the beta-agonist. They did not get better when they stopped the beta2-agonist; whereas, the arginine/arginine patients did improve when they stopped the beta-agonist, before the crossover period. These findings suggest that arginine/arginine patients might benefit either by discontinuing use of albuterol as a rescue inhaler and using it as a prn adjuvant (as used in the study) or by using prn albuterol; and that patients who are arginine/arginine should never use beta-agonists every day on a regular basis.

There are studies that have looked at LABAs, but retrospectively. Two studies were published in the American Journal of Respiratory and Critical Care Medicine in 2006. The first study was the Salmeterol Or Corticosteroids (SOCS) study. This is a 28-week, randomized, double-blind, placebo-controlled, parallel-group study comparing LABA monotherapy with continued therapy with inhaled corticosteroids. After 6 weeks on an open-label inhaled corticosteroid, patients (for 16 weeks) got either: inhaled corticosteroids twice a day; salmeterol as monotherapy; or they got placebo. The trial concluded with a 6-week, single-blind, placebo run-out, albuterol used prn. Retrospectively, they went back and genetically typed the polymorphic beta-receptor in a number of patients. You can see here that the morning peak flow increased in salmeterol-treated patients with the glycine/glycine genotype, but declined in the arginine/arginine patients compared with placebo, suggesting that thearginine/arginine patients taking a LABA would experience an adverse effect in their morning peak flow. The study concluded that patients with persistent asthma who were well controlled on low-dose inhaled corticosteroids should not be switched to salmeterol monotherapy, because there was a risk of clinically significant loss of control. There was a much greater loss of control if the patients had the arginine/arginine genotype.

The second study was the Salmeterol With and Without Inhaled Corticosteroids (SLIC) study. These were patients who were on salmeterol with or without inhaled corticosteroids, in the same type of study. They were on inhaled corticosteroids at run-in, and then they received either salmeterol or placebo with their inhaled corticosteroids. Half the patients were randomly assigned to maintain inhaled corticosteroids throughout the trial, or to undergo a blinded reduction in their inhaled corticosteroid while they were just on salmeterol monotherapy. This was a complicated analysis, but the same thing was done. They went back and genotyped these patients, their beta-receptor; again their primary endpoint was morning peak flow. There was an initial benefit with the addition of salmeterol to the arginine/arginine patients; by the end of 18 weeks, the morning peak flow deteriorated. The glycine/glycine patients, on the other hand, had sustained beneficial effects of salmeterol.Retrospective analysis of the genotypes in the SLIC and SOCS studies suggests that asthmatic patients with the arginine/arginine genotype may have an impaired therapeutic response to salmeterol, in either the absence or the presence of inhaled corticosteroid. So whether they are on inhaled corticosteroids or not, the use of salmeterol has an adverse effect in patients with the arginine/arginine genotype.

There was another retrospective analysis that did not show the adverse effect of salmeterol in the arginine/arginine group. They only had a problem when they were treated. If you look at this slide, the first bar is placebo; the second bar is albuterol, which is salbutamol; and the third bar is salmeterol. In this UK study, only the arginine/arginine with the short-acting beta-agonist had an adverse effect on the exacerbations. So not all studies have shown that the arginine/arginine patients have an adverse effect with salmeterol alone; but, there is no question that short-acting beta-agonists are always a risk when taken regularly.

What are the implications of this? Analysis suggests that arginine/arginine patients do not benefit from the use of salmeterol. These patients may develop worsening airway function with the chronic use of LABAs. Until we can do adequate genotyping, we do not know who those patients are, but 1 out of 5 patients, African Americans, and 1 out of 6 Caucasians had the arginine/arginine polymorphic receptor.

What are the conclusions? It is critically important to assess asthma severity and control, select therapy that is appropriate for each individual patient, and always consider inhaled corticosteroids for persistent asthma.

LABAs may increase the risk of severe asthma, exacerbations, or death in some patients; this may be due in part to genetic polymorphism in the beta2-adrenergic receptor. It is important to talk to your patients about the LABA issue. You should always consider more aggressive inhaled corticosteroid monotherapy in patients with worsening asthma while taking LABAs, or consider not using LABAs.

LABAs are valuable tools for asthma management but should only be used appropriately in clinical practice. They should never be first line for patients with mild asthma or for patients with moderate asthma. LABAs are not appropriate in patients whose asthma worsens while taking chronic LABAs. One may need to consider that the LABAs may be making them worse; one may want to consider either increasing the inhaled corticosteroid while stopping the LABAs and/or adding a leukotriene modifier or theophylline.

I have covered a lot of material, and hopefully, you have acquired a significant knowledge about asthma management and the controversial issue of LABAs and short-acting beta-agonists on the adverse effect of asthma.