Using controller therapy in the management of asthma
Dr Storms: Given that a patient's asthma varies quite a bit from day to day, and that controller therapies can prevent exacerbations, is there any role for using a controller medication as-needed rather than using it regularly? Could exacerbations be prevented if the patient has been educated to start treatment as soon as symptoms occur or peak expiratory flow (PEF) falls?
Dr Storms: Given that a patient's asthma varies quite a bit from day to day, and that controller therapies can prevent exacerbations, is there any role for using a controller medication as-needed rather than using it regularly? Could exacerbations be prevented if the patient has been educated to start treatment as soon as symptoms occur or peak expiratory flow (PEF) falls?
Dr Fuhlbrigge: Our recent analysis that compared consistent users of controller therapy with those who used such therapy less consistently showed that consistent use was beneficial.1 Perhaps well-educated patients who clearly know when to start treatment would be able to use this as-needed approach to prevent exacerbations. Physicians would have to make this decision on a case-by-case basis.
Dr Peters: I think that putting the decision to escalate or de-escalate therapy in patients' hands, on the basis of defined clinical parameters, is likely to benefit many patients. This was suggested by data on the use of combination therapy with the inhaled corticosteroid budesonide and the long-acting ß2-agonist formoterol.2 This study involved an adjustable maintenance paradigm and use of a single inhaler for both maintenance and rescue therapy.
Dr Deykin: The combination inhaler may suggest a way for patients to use more medication when they need it. With the single inhaler, the decision is somewhat removed from the patients. They do not exactly "decide" when to increase or decrease the inhaled corticosteroid dosage; their symptoms determine this.
It seems clear, however, that when patients double their dosage of inhaled corticosteroids in response to a flare-up of symptoms, they are unable to abort asthma attacks. It is not clear whether this is because they act too late or whether the additional dosage is not effective.
Dr Fuhlbrigge: I suspect that many patients act too late. Patients cannot necessarily abort an exacerbation if they wait until symptoms become bothersome.
Dr Peters: Also, the evidence suggests that the dosage of inhaled corticosteroids would have to be increased about 4 times to abort an asthma attack. Doubling the dosage never seems to work.
Dr Deykin: The IMPACT trial was informative because it revealed that many patients ignored the instruction to take action on the basis of symptoms.3 This occurred despite the fact that patients were closely monitored, were instructed repeatedly on the use of these agents, and were given medication to have available. It is not clear whether the additional step of having to decide to activate a plan would be too much of a hurdle for patients.
Adjusting medication on the basis of symptoms might be helpful, but the idea of autotitrating or titrating therapy on the basis of a parameter other than symptoms is intriguing. We are starting to see some data that indicate that the measurement of inflammatory markers may allow titration of inhaled corticosteroid dosages, with good results and use of much lower dosages overall, compared with the guidelines approach.4 It would be interesting to compare an inflammatory marker-based titration algorithm with a symptom-based, patient-driven algorithm.
Dr Fuhlbrigge: When we discuss the use of inflammatory markers as a basis for adjusting therapy, however, it is important to consider how accessible those markers are in clinical practice.
Dr Deykin: That is a major barrier. Even the daily measurement of PEF has modest value for primary care practitioners, mostly because many patients will not measure their PEF. Nonetheless, assessing PEF variability is an element in the current asthma guidelines; physicians are supposed to monitor PEF and respond accordingly.5
I would also like to point out that the "number-needed-to-treat" issue is very important. A certain number of patients do not really need--or are not going to respond to--their prescribed medication, but we do not know how to identify them. We also know that patients' status can change, and they may need and respond to therapy at another time. These issues are difficult to sort out. If we could identify those who are very unlikely to need therapy, this would dramatically change the number-needed-to-treat ratio.
Airway remodeling
Dr Storms: Many of my primary care colleagues mention the topic of airway remodeling when we discuss asthma therapy. Some of them seem to have concluded that patients need to regularly take inhaled corticosteroids to prevent airway remodeling.
Dr Fuhlbrigge: One major study that has significantly influenced our understanding of the effect of inhaled corticosteroids on airway remodeling is the CAMP (Childhood Asthma Management Program) study.6 Another major study is the PEAK (Prevention of Early Asthma in Kids) trial.7 The find-ings suggest that inhaled corticosteroids do not have a permanent effect on lung function, even when therapy is initiated in young children. Although inhaled corticosteroids are considered disease-modifying agents, their effects wane after they are discontinued.
Dr Peters: It depends on what is meant by "disease-modifying." Corticosteroids have salutary effects in some patients, but there certainly is no strong evidence that therapy changes airway remodeling. Even the evidence that prolonged inhaled corticosteroid therapy has a structural effect on the airways is very weak.
Adverse effects and cost-effectiveness
Dr Fuhlbrigge: Two issues that were raised concerning the use of controller therapy were toxicity and cost. There has been concern about the potential adverse effects of inhaled corticosteroids on bone density, and the analysis by Israel and his group8 did find a significant adverse effect. However, a systematic review of the literature reveals a wide range of potential effects of inhaled corticosteroids on bone density.
In evaluating the cost-effectiveness of controller therapy, the analysis should take into account the entire spectrum of effects. A dramatic impact on cost-effectiveness is seen only when the analysis focuses on the very extreme estimates in the literature. An analysis has to weigh the risks and the benefits and consider the possible trade-offs. With respect to corticosteroids, the potential risk of hip fracture may be small, and this risk has to be weighed against the potential loss of asthma control. When all of the costs are considered, the impact of inhaled corticosteroids on potential hip fractures may not be very dramatic in patients with mild to moderate asthma.
Leukotriene modifiers do not appear to have adverse effects on bone density. However, for patients with severe asthma, the data suggest that inhaled corticosteroids may be more effective than leukotriene modifiers.9 Therefore, it is important to target your patient population appropriately--which controller to use and when.
Dr Deykin: I agree. The primary concern is for patients who are using high doses of inhaled corticosteroids for a long period. However, the data emphasize that there is no "free lunch." The risks of hip fracture may be outweighed by the benefits of therapy for some patients. However, for patients who do not require inhaled corticosteroids to achieve acceptable control of their asthma, there is no rationale for exposing them to the risks or expense of these agents. The key is to refine our understanding of asthma severity and risk, so that we can give the best therapies to the patients who need them and avoid giving therapies to those who do not really require them.
Managing asthma in the primary care setting
Dr Storms: Most patients with asthma are taken care of by primary care physicians, who often have to treat asthma as an acute rather than chronic disease. What is the most useful information that will help physicians prevent exacerbations and emergency department visits in their patients with asthma?
Dr Deykin: If a patient has required a fair amount of medication because of an exacerbation, I would attempt to reduce the medication after the asthma has stabilized. The fact that the patient has had an exacerbation does not mean that controller therapy has to be continued indefinitely. However, I would consider this approach only for patients who can be monitored closely.
Dr Peters: In deciding whether medication can be reduced, I find it very useful to measure the forced expiratory volume in 1 second (FEV1). The patients whose asthma appears to be well-controlled usually have good pulmonary function--an FEV1 of about 90% of predicted. Patients who do not have good pulmonary function are not usually candidates for intermittent therapy.
Dr Storms: It does seem clear that all patients with asthma should undergo spirometry. I also think that all patients should be given an asthma control questionnaire, such as the Asthma Control Test (ACT).
Dr Fuhlbrigge: Using tools such as the ACT and the Asthma Control Questionnaire (ACQ) can make it easier for primary care physicians to treat asthma as a chronic disease.10,11 The ACT, for example, can be easily administered in the office; in fact, patients can fill it out in the waiting room. Both the ACT and the ACQ can provide a quick and easy way for practitioners to assess how well the patient's asthma is being controlled.
In addition, the Asthma Therapy Assessment Questionnaire (ATAQ) has been developed by Vollmer and colleagues.12 Cross-sectional analysis has demonstrated significant associations between ATAQ score and health care utilization and generic and disease-specific quality of life.
Dr Deykin: Using these questionnaires is certainly a lot easier than trying to apply the National Asthma Education and Prevention Program guidelines5 for stratifying asthma severity.
Dr Peters: The initial attempts at stratifying asthma severity produced a very complicated schema, which I think has failed in clinical practice. Incidentally, the ACQ has not yet been validated for individual patients and the ACT is undergoing validation.
One final point I would add about controlling asthma is that for patients whose asthma is not adequately controlled by moder-ate-dose inhaled corticosteroids, adding another agent is usually preferable to increasing the dosage of the inhaled corticosteroid to a very high level. This has been most convincingly shown by adding a long-acting ß2-agonist, although adding a leukotriene modifier has also been shown to be a reasonable alternative.
The decision about which agent to add can be based on individual patient characteristics. Patients who have more severe bronchospasm, for example, might be better candidates for a long-acting ß2-agonist, while those with an allergic component to their asthma, including those who also have allergic rhinitis, might be better candidates for a leukotriene modifier. The leukotriene modifier montelukast, for example, has been approved for the treatment of allergic rhinitis as well as for asthma.
References:
REFERENCES
1. Fuhlbrigge AL, Stempel DA, McLaughlin T, Stanford RH. Relative risk of asthma-related emergency department/hospitalization events with consistent, adjustable, or intermittent inhaled corticosteroids (ICS).
Am J Respir Crit Care Med.
2005;2:A363.
2. O'Byrne PM, Barnes PJ, Rodriguez-Roisin R, et al. Low dose inhaled budesonide and formoterol in mild persistent asthma. The OPTIMA randomized trial.
Am J Respir Crit Care Med.
2001;164:1392-1397.
3. Boushey HA, Sorkness CA, King TS, et al. Daily versus as-needed corticosteroids for mild persistent asthma.
N Engl J Med.
2005;352: 1519-1528.
4. Deykin A, Lazarus SC, Fahy JV, et al. Sputum eosinophil counts predict asthma control after discontinuation of inhaled corticosteroids.
J Allergy Clin Immunol.
2005;115:720-727.
5. National Asthma Education and Prevention Program report: guidelines for the diagnosis and management of asthma update on selected topics--2002.
J Allergy Clin Immunol.
2002; 110(suppl):S141-S219.
6. Childhood Asthma Management Program Research Group. Long-term effects of budesonide or nedocromil in children with asthma.
N Engl J Med.
2000;343:1054-1063.
7. Guilbert TW, Morgan WJ, Krawiec M, et al. The Prevention of Early Asthma in Kids study: design, rationale and methods for the Childhood Asthma Research and Education network.
Control Clin Trials.
2004;25:286-310.
8. Israel E, Banerjee TR, Fitzmaurice GM, et al. Effects of inhaled glucocorticoids on bone density in premenopausal women.
N Engl J Med.
2001;345:941-947.
9. Ducharme FM, Hicks GC. Anti-leukotriene agents compared to inhaled corticosteroids in the management of recurrent and/or chronic asthma in adults and children.
Cochrane Database Syst Rev.
2002;3:CD002314.
10. Nathan RA, Sorkness CA, Kosinski M, et al. Development of the asthma control test: a survey for assessing asthma control.
J Allergy Clin Immunol.
2004;113:59-65.
11. Juniper EF, O'Byrne PM, Guyatt GH, et al. Development and validation of a questionnaire to measure asthma control.
Eur Respir J.
1999; 14:902-907.
12. Vollmer WM, Markson LE, O'Connor E, et al. Association of asthma control with healthcare utilization and quality of life.
Am J Respir Crit Care Med.
1999;160:1647-1652.
