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DR. SOPHOCLES: What are the current treatment recommendations from the NHLBI expert panel?
DR. COX: In the previous guidelines, asthma medications have been divided into two categories and this remains. There is a category referred to as the controller medications and they’re used daily to achieve and maintain asthma control. And these include corticosteroids, oral and inhaled, Cromolyn sodium and nedocromil, which are non-steroid anti-inflammatory medications, immunomodulators— and this is a new category in this guideline— leukotriene modifiers, long-acting beta2-agonists, and Methylxanthines.

In the new class of long-term controller medications, the immunomodulators, the one drug that has proven efficacy in asthma is Omalizumab, and it is a monoclonal antibody against IgE. Other agents have been investigated but to date have not shown significant clinical efficacy in asthma, and these include anti-TNF agents, soluble interleukin 4, Anti-L IL-5, Recombinant IL-12, and Intravenous immunoglobulin.

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DR. SOPHOCLES: What are the current preferred medications for controlling asthma?
DR. COX: Inhaled corticosteroids in the previous guidelines were the preferred controller drug for all ages of persistent asthma—and they remain the preferred controller drug in this current document. They are the most effective long-term therapy available for mild, moderate, or severe persistent asthma and are generally well-tolerated and safe at recommended doses. The potential, but small risk of adverse events from these inhaled corticosteroids is well balanced by their efficacy. The dose response curve for inhaled corticosteroid treatment begins to flatten for many measures of efficacy at low to medium doses, although some data suggest that higher doses may reduce the risk of exacerbation. Once you are in the higher dose range, you may be seeing some systemic effects of the inhaled corticosteroids. Most benefits are achieved with relatively low doses of inhaled corticosteroids, whereas the risk of adverse effects increases with dose.

The adverse effects of concern are vertical growth in children—and the potential of growth velocity during the first year of treatment with low-to-moderate inhaled corticosteroids—seems to only be limited to the first year. In subsequent years, this effect is lost and children on low-to-moderate doses of inhaled corticosteroids have been shown in several studies to achieve their predicted adult height. The recommendations in the guidelines are that physicians who treat children and adolescents with inhaled corticosteroids by any route should monitor their growth on a regular basis.

The other side effect of concern is bone mineral densities. Studies, including six years of observation in children, have not seen any adverse effects on bone mineral density in low-to-moderate doses of inhaled corticosteroid. However, a small dose-dependent reduction in bone mineral density has been associated with inhaled corticosteroid use in patients older than 18 years of age.

Ocular toxicity is another concern. Low-to-moderate doses of inhaled corticosteroids had no significant effects on the incidence of subcapsular cataracts or glaucoma according to six years of observational studies. In adults, high cumulative lifetime exposure, which is greater than 2,000 milligrams of beclomethasone dipropionate or equivalent, may increase the prevalence of cataracts as suggested in three retrospective studies of adults and elderly patients. One retrospective case-control study showed an association between long-term inhaled corticosteroid use and the development of glaucoma. So there is a hint that with high doses over long periods of time, there may be some associated ocular toxicity in terms of glaucoma and cataracts.

So, in summary, there may be a slight risk of decreased bone mineral density in adults which appears to be dose related. There also may be a slight risk of ocular toxicity in terms of glaucoma or cataracts, again, that is likely to be dose related. There has been no evidence of significant bone mineral density loss in children in studies that lasted as long as six years. There is some effect on growth that appears to be limited to the first year, but the predicted adult height in children does not appear to be effected by inhaled corticosteroids at low to medium doses.

The preferred add-on medication to a failed inhaled corticosteroid regimen for adults is long acting beta-agonists. There is, however, some controversy about these due to some recent studies. The side effects of beta-agonists of concern are: it is a stimulant medication so tachycardia may be one of the side effects. This is generally transient and with regular use this side effect does disappear within a few weeks. Other side effects could be tremors, cramps, insomnia, increased plasma glucose and at high doses low potassium. There is desensitization and down-regulation of the beta-receptor with regular use to some extent, and that term is referred to as tachyphylaxis.

In the expert panel guidelines report, they note that long-acting beta-agonists is the preferred treatment as an add-on to inhaled corticosteroids in use by those twelve years or greater and adults. However, safety issues have been raised regarding the long-acting beta-agonists. The established beneficial effects of long-acting beta-agonists for the great majority of patients who have asthma is not significantly controlled with inhaled corticosteroids alone and should be weighed against the increased risk for severe exacerbations, although uncommon, associated with the daily use of long-acting beta-agonists.

The controversy with long-acting beta-agonists primarily stem from a study referred to as the SMART study. This was a 28-week, multi-center, randomized, double-blind, placebo-controlled, observational surveillance trial initiated in July of 1996. There were 6,163 US sites and 1,316 investigators. The target enrollment was 60,000 patients who were greater than 12 years of age with asthma and currently using prescription asthma medications. There was no history of previous salmeterol or formoterol use and all therapies were taken on an outpatient basis.

This study design was such that they received either salmeterol 42 micrograms twice a day and their usual care, or placebo twice a day and their usual care for a 28-week period. There was phone contact every four weeks.

The primary endpoints were respiratory death and severe asthma exacerbation. When they analyzed the data, they found in the group that received almeterol there was a higher incidence of respiratory deaths. When they looked at it according to race, you can clearly see that there was a higher incidence of respiratory death or life-threatening experience in the African-American population.

In the African-American population, the incidence was 20 patients out of 2,366 in the salmeterol group, versus 5 out of 2,319 in the placebo group, giving it an odds ratio of salmeterol being linked

with respiratory death of 4.0, whereas in the Caucasian population, it was 29 deaths in 9,281 in the salmeterol and 28 deaths out of 9,361 in the placebo group with a odds ratio of 1.0.

In conclusion, short-acting beta-agonists are the drug of choice for acute symptomatic relief. There are controversies that exist about the value of adding routine long-acting beta-agonists therapy. Maybe the genotyping at the betareceptor locus, looking at the Arg/Arg and the Gly/Gly phenotype, might help us stratify the risks for these beta-agonist medications. Clearly, further studies are needed to help us understand who may benefit and who may not benefit from long-acting beta-agonists.

The other commonly prescribed add-on therapy to a failed inhaled steroid regimen is leukotriene receptor antagonists. Expert Panel 3 recommends that leukotriene receptor antagonists are an alternative, but not preferred, treatment option for mild persistent asthma. They can be used as an adjunct therapy with inhaled corticosteroids, but for youths 12 years and older and adults, they are not the preferred adjunct therapy compared with the addition of the long-acting beta-agonists. The 5-lipoxygenase inhibitor, zileuton, is an alternative treatment option that is less desirable than leukotriene receptor antagonists due to more limited efficacy data and the need for ongoing liver function monitoring.

As monotherapy, a few studies have compared leukotriene antagonists with inhaled corticosteroids. Three randomized, controlled, double-blind studies in children 5-15 years of age demonstrated greater effectiveness of inhaled corticosteroid with fluticasone compared to montelukast. They found significantly improved lung functions and total symptom scores, as well as reduction in exacerbation in the inhaled corticosteroid group compared to the montelukast group.

One of these three studies demonstrated the montelukast was not inferior to fluticasone in rescue-free days, but the other two showed superiority of fluticasone compared to montelukast for percentage of rescue-free days. These were the studies cited in the expert panel guideline that supported the rationale for not having leukotriene antagonists as monotherapy for persistent asthma.

One study attempted to identify biomarkers that might predict who would respond to inhaled steroids or leukotrienes. They recruited children 6-17 years of age with mild to moderate persistent asthma and randomized them to one of two cross-over

sequences including 8 weeks of an inhaled corticosteroid, in this case fluticasone—again, 100 mcg twice a day—and 8 weeks of a leukotriene receptor antagonist, montelukast, 5-10 mg nightly depending on their age, in a 18-week trial. Response was assessed on the basis of improvement in FEV1 and in terms of the relationship to baseline asthma phenotype. They defined significant response as improvement in FEV1 of 7.5% or greater. Seventeen percent of the 126 participants responded to both medications, 23% responded to fluticasone alone, 5% responded to montelukast alone, and 55% responded to neither medication.

A favorable response to fluticasone alone was associated with higher levels of exhaled nitric oxide, total eosinophil count, serum IgE, and level of serum eosinophilic cationic protein or ECP, and lower levels of methacholine, and pulmonary function tests. Favorable response to montelukast alone was associated with younger age and shorter disease duration.

This is a diagram that graphs these results, again demonstrating that 55% responded to neither, 5% responded to the leukotriene receptor antagonist, and 7% responded to both. The last asthma treatment therapies that I’m going to discuss are new to the expert panel guideline treatment tables and that is Omalizumab and Allergen Immunotherapy.

DR. SOPHOCLES: How does Omalizumab work?
DR. COX: Omalizumab is a monoclonal antibody that is 95% human and 5% murine that is directed against IgE. Omalizumab binds to the portion of IgE that binds to the Fc receptor on the mast cell or the basophil, and what this does is essentially prevent IgE from binding to the mast cell or the basophil and therefore prevents the allergic reaction from happening.

So what Omalizumab will do is, it will bind circulating IgE, prevent it from binding to the mast cell, and the complexes will be eventually cleared through the spinal endothelial system. Over time, because the IgE is no longer circulating, the mast cell and basophils are losing a positive feedback—which is the IgE—so it stops producing the high affinity IgE receptors. There is a downstream effect several months later in that there is downregulation of the IgE receptors. In essence what you have done with this monoclonal antibody is knock out the allergic component of asthma.

There was a study called the INNOVATE study. It was a randomized, 28-week, double-blind, parallel group study that looked at groups that were not well controlled with inhaled corticosteroids and long-acting beta-agonists. They had a recent history of clinically significant exacerbations and were randomized to receive Omalizumab or a placebo. The primary outcome was asthma exacerbations requiring systemic corticosteroids.

They found there was a significant reduction in asthma exacerbations in the group that received Omalizumab, 26%, and this was statistically significant when adjusted for the baseline severity prior to enrolling in the study. Without this adjustment, there was still a 19% reduction, but it was not statistically significant. This study would suggest that Omalizumab added to a failing long-acting beta-agonist inhaled corticosteroid regimen provides some additional improvement; and no other studies have really done that with the other add-on medications such as leukotriene antagonists and theophylline.

There have been also a number of other studies that have consistently demonstrated reduction in asthma exacerbations and need for medications with this Omalizumab compared to a placebo.

There are two safety concerns with this particular medication: one is that in the initial clinical trials, there was a slightly greater incidence of malignancies identified, most of them in the first six months. In the group that received Omalizumab the incidence was .5% and that compared with .2% of the patients that received placebo. This was carefully analyzed by several blinded oncology boards and it was felt that there was no link between the cancers that were identified. There was no common thread, and it was felt that this could not be cause and effect. There is an ongoing study that is looking at the safety in terms of malignancy and data is being collected on this.

Recently a black box warning was added to Omalizumab concerning the risk of anaphylaxis because there were some cases reported in the post-marketing surveillance after the medication was approved. The incidence of anaphylaxis in an analysis that was performed by the FDA was approximately .2%, so the incidence is still fairly low. There are some who think that the malignancy difference may have just been the randomization, but apparently .5% is the expected malignancy rate for that age population, so the Omalizumab-treated patients actually had what would be expected in terms of malignancy rate for that age population. In the controller placebo group, .2% was actually lower than expected.

The other treatment regimen that’s new in the treatment table of the expert panel guidelines is actually a very old treatment and that’s allergen immunotherapy. But in previous documents, it was mentioned in the narrative but not included in the treatment tables.
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DR. SOPHOCLES: How does Allergen Immunotherapy work?
DR. COX: Allergen immunotherapy is the only disease-modifying treatment for allergic asthma. It should be considered if there is a clear relationship between asthma symptoms and the allergen exposure. It is usually reserved for patients who have year-round symptoms and difficulty managing their symptoms due to a need for multiple medications, poor adherence to medications, or suboptimal response to medication—and this is directly from the expert panel document.

There has always been some debate about the effectiveness of allergen immunotherapy in asthma, but there have been several meta-analyses that have confirmed its efficacy. The most recent meta-analysis was a Cochrane Review published in 2003. It analyzed 75 trials with a total of 3,188 asthmatics and found that there was a considerable heterogeneity among these studies.

Overall there was a significant improvement in asthma symptom scores; and it would be necessary to treat four patients with immunotherapy to avoid one deterioration in asthma, and to treat five patients with immunotherapy to avoid requiring increased medications. These numbers are pretty impressive. Their conclusion was that immunotherapy reduces asthma symptoms and use of asthma medications, and improves bronchial hyper-reactivity. However, there was no consistent effect on lung function, though there was improvement in allergen specific bronchial hyper-responsiveness. In other words when they challenged the individual with the allergen to which they were receiving immunotherapy, there was an improved response on these challenges. The report also noted the possibility of adverse effects (such as anaphylaxis) which must be considered.

The incidence of adverse reactions depends on the study. For allergen immunotherapy injections, the rate is probably about .5% of injections, but most of those are mild. Severe reactions—near fatal as they were described in one survey—occurred at a rate of 5 per 1 million injections and surveys that have looked at asthma fatalities have reported a death rate of between 1 in 2 million to 2 ½ million injections per year. So these are very rare events.

Overall, the NHLBI expert panel treatment guidelines are summarized in a series of tables. The treatment tables are based on the three age stratifications that I mentioned previously, and there are different tables for initiating treatment and then for evaluating patients who are on treatment. Again, these can be downloaded from the website and I strongly encourage you to do so because this is an excellent resource for determining and making decisions about asthma treatment.

The first table is a guide to treatment for children age 0-4. Now remember, we previously had a table that helped us define their severity, so now that we’ve defined their severity, we can look and determine what are the recommended treatment options for these children. As you can see, there are six steps to treatment. This is different from previous guidelines because the previous guidelines only had four steps, so there are actually additional steps in this step-wise approach to treatment.

The next table is a treatment table that helps you assess control of children who are on therapy. It is similar to what we had previously looked at in terms of the frequency of symptoms, but the difference is at the end of this table. It gives you a recommended action for treatment, depending on whether the child is well-controlled or not well-controlled or very poorly controlled. One of the recommendations in terms of evaluating somebody who is not well-controlled is that you re-evaluate them 2-to-6 weeks after initiating treatment. The other recommendation is that when somebody has been stable for a period of 3 months, that would be when you would consider stepping down or modifying your treatment. So it gives you some timeline in the document about when you should be re-evaluating the patient and making treatment decisions.

Then we move on to the treatment table for children 5-11. Again, we have six steps with inhaled corticosteroids as the preferred controller therapy for every level. At step three, which they reach if they failed low dose inhaled corticosteroids, add-on therapy could be a long-acting beta-agonists, a leukotriene receptor antagonist, or theophylline. Step four is a little different from the 0-4 because now long-acting beta-agonists become the preferred add-on in this age group.

The next slide looks at the assessment of the child on therapy age 5-11 on their follow-up visit. It is very similar again to the previous slide with children 0-4 when you’re assessing them. You have the impairment and risk domains that you look at, and then you have some recommendations for what step of therapy they should be on depending on where their level of control is. And again, the same recommendations—re-evaluate them after 4-6 weeks and consider adjusting therapy if they haven’t reached their goal at that point in time. The recommendation is to consider keeping them on therapy for 3 months before considering stepping down and showing that they’re stable on therapy.

The next slide is the youths and adults 12 and greater treatment table, and this is a little different. Again we have six steps, with inhaled corticosteroid as the preferred controller medicine; but at step three when you fail low dose inhaled steroids, long-acting beta-agonists are considered one of the add-ons, or medium inhaled corticosteroids. This is different from the previous guidelines whereas if you failed low dose inhaled steroids, the preferred next step would be to add the long-acting beta-agonist, and the difference here is that you have an equal option of increasing the inhaled steroid. Then when you go to step four, the adding-on of the long-acting beta-agonist is the preferred step. What is different in this table and unique is on step five, and that would be for the person who is failing a medium-dose inhaled steroid and a long-acting beta-agonist, you would consider Omalizumab for patients who have allergies.

So there is a new drug in this treatment table for youths 12 and older and adults. The other thing that is new about this table is that in the box that runs underneath all the steps it says “patient education, environmental controls, and management of comorbidities,” but under that it says steps 2 through 4 consider subcutaneous allergen immunotherapy for patients who have allergic asthma. So that is a new addition to the treatment table.

Then for assessing adults that are on therapy, there is another treatment table on the following page, similar design to the previous two, again with the classification system being fairly similar; how frequently do they wake up at night? how frequently do they need their beta-agonist? We have the validated questionnaire with the grading system and it is recommended that you obtain or use one of these questionnaires when you evaluate patients in follow-up. And then there are the guidelines for stepping up or down treatment depending on their level of control on that office visit.