Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

Based on the following articles: Kuna et al. Int J Clin Pract 2007;61(5):725-36. Bousquet et al. Respir Med 2007; 101:2437-46. Vogelmeier et al. Eur Respir J 2005;26:819-28.

Reviewed by: Louis-Philippe Boulet, MD, FRCPC

Institut de cardiologie et de pneumologie Hôpital Laval Quebec City, Quebec

Professor of Medicine Université Laval Quebec City, Quebec

The prevalence of asthma is increasing in both sexes in Canada, though more so in men (Respiratory Disease in Canada, Health Canada, September 2001), and there are few signs that asthma control is significantly improving. According to the Reality of Asthma Control survey by McIvor et al. (Can Fam Physician 2007; 53:672-7), 53% of 893 adults surveyed had uncontrolled asthma based on objective criteria of the Canadian Asthma Consensus Guidelines. Over 80% of the same survey group reported that there were times when their symptoms became worse. For those with uncontrolled asthma, exacerbations led to substantially greater use of health care resources than for those whose asthma was controlled.

The Canadian Lung Association also maintains that asthma is the number one cause of emergency room (ER) visits and that approximately 500 adults die from asthma each year—despite guidelines that recommend aggressive management beyond the mildest forms of the disease.

As it turns out, poor asthma control has less to do with the medications used than the way in which patients use or misuse them. In a literature review undertaken to better understand patient compliance, lead author Lacasse et al. (Can Respir J 2005;12(4): 211-7) found that fewer than half of patients who had been prescribed an inhaled corticosteroid (ICS) for maintenance therapy took the medication as prescribed; about one in four were taking almost no medication at all; and a similar number of patients were using their inhalers only occasionally. Fear of weight gain and other potential side effects, and complexity of therapy can affect adherence to ICS, among other factors.

One approach that has become popular is to treat asthma with a fixed combination of an ICS and a long-acting beta2-agonist (LABA) plus a short-acting beta-agonist (SABA) for symptomatic relief. As pointed out by Vogelmeier et al. (Eur Respir J 2005;26(5):819-28), not only are fixed-combination inhalers more convenient than separate inhalers, but they can often control asthma at lower doses of ICS compared with ICS therapy alone. Currently, two ICS/LABA combination inhalers are available: budesonide/formoterol and salmeterol/fluticasone, both of which are used as maintenance therapy, along with a separate SABA as needed for symptom relief.

A number of investigators have proposed that the ICS/LABA combination be used for both maintenance and reliever therapy, obviating the need for SABA as rescue medication. This simplified strategy must be able to offer rapid onset of action, as rapid symptomatic relief is clearly needed in asthma management.

Combination budesonide/formoterol is the only treatment that can fulfill these criteria, combinations containing salmeterol having a slower onset of action (Eur Respir J 1997;10:2484-9). The fixed-combination inhaler as both maintenance and reliever therapy—the SMART (Symbicort Maintenance and Reliever Therapy) strategy—has interesting characteristics and potentials. First, patients cannot increase their exposure to beta-agonist therapy without concomitantly increasing their exposure to ICS. If they are using their as-needed medication because of declining asthma control—as is very often the case—evolving exacerbations will possibly be treated at an early stage and a further worsening of asthma may possibly be prevented. Patients also need only a single inhaler to meet their medical needs. There are also possible cost advantages vs. standard recommended alternatives.

Combination Approaches to Asthma: COMPASS, AHEAD, COSMOS

Evidence has been accumulating that the SMART approach to asthma management offers control comparable to widely recommended alternatives, often at lower overall doses of ICS. Three pivotal studies have explored SMART in patients with asthma.

In the COMPASS study (Kuna et al. Int J Clin Pract 2007;61(5):725-36), 3335 symptomatic adolescents and adults were randomized to one of three cohorts: budesonide/formoterol 160/4.5 µg in a single inhalation b.i.d. plus additional as-needed inhalations; the fixed-dose combination of salmeterol/fluticasone 25/125 µg in two inhalations b.i.d. plus terbutaline; or a comparable fixed maintenance dose of budesonide/formoterol 320/9 µg in a single inhalation b.i.d. plus terbutaline, again on an as-needed basis. The primary end point of COMPASS was time to first severe exacerbation, defined as deterioration in asthma resulting in hospitalization or ER treatment or the need for oral steroids for three or more days.

At the end of 24 weeks, investigators found that SMART prolonged the time to first severe exacerbation compared with the fixed-dose/SABA strategy, reducing the hazard ratio for a first severe exacerbation by 33% (P=0.003) compared with salmeterol/fluticasone, and by 26% compared with fixed-dose budesonide/formoterol (P=0.026). The two fixed-dose groups did not differ with respect to time to first severe exacerbation.

SMART also reduced the total number of severe asthma exacerbations by 39% compared with fixed-dose salmeterol/fluticasone (P<0.001) and by 28% compared with fixed-dose budesonide/formoterol (P=0.0048). The total number of hospitalizations/ER episodes was also reduced in both budesonide/formoterol groups relative to fixed-dose salmeterol/fluticasone but the difference between the two budesonide/formoterol groups was not statistically significant.

Investigators also reported that SMART patients required 41% to 45% fewer days on oral steroids compared with both fixed-dose regimens, and that SMART also reduced the number of days with exacerbations requiring hospitalization/ER visits by 38% to 61%. All three regimens provided similar improvements in symptom control and there were no differences in lung function between the different treatment arms. All three regimens were equally well tolerated. Significantly, however, SMART achieved improvements in asthma control at a 50% reduction in regular maintenance doses of the ICS/LABA compared with the other two regimens.

AHEAD Results

As lead investigators of the Canadian arm of the recently published AHEAD study (Bousquet et al. Respir Med 2007;101:2437-46), we randomized a total of 2309 patients who had experienced at least one asthma exacerbation in the previous year to the SMART strategy, this time consisting of budesonide/formoterol 160/4.5 µg in two inhalations b.i.d. and as needed, or to one inhalation of high-dose salmeterol/fluticasone 50/500 µg b.i.d. plus terbutaline, as needed. Treatment was continued for six months.

The primary outcome measure in AHEAD was again time to first severe exacerbation (as defined in the COMPASS trial). Secondary outcomes included the rate of severe exacerbations, the time to first hospitalization or ER treatment and the rate of hospitalizations or hospitalizations and ER treatments.

At the end of six months, the time to first severe exacerbation was not significantly longer among SMART recipients. Nevertheless, SMART tended to prolong the time to first and repeat exacerbations and was associated with a 21% reduction in the overall exacerbation rate (25 events/100 patients/year) compared with high-dose salmeterol/fluticasone plus SABA at 31 events/100 patients/year (P=0.039). SMART also reduced the risk of patients requiring hospitalization or ER treatment by 36% vs. the comparator arm, and there was a 31% reduction in the rate of hospitalization/ER treatment in favour of the budesonide/formoterol maintenance and as-needed arm (P=0.046).

Importantly, however, equal improvements in asthma control were achieved with a 38% lower mean daily dose of ICS in the budesonide/formoterol group vs. the salmeterol/fluticasone group, a difference which was significant (P<0.0001). Patients in the SMART arm also required fewer days of oral steroid use due to exacerbations (764 days) vs. 990 days in the fixed-dose/SABA arm. Rates of serious adverse events were both very low and similar between the two groups. Again mirroring findings from COMPASS, both groups in AHEAD experienced similar improvements in daily symptom control to approximately 44 days at study end point, up from about six days at baseline. There were no differences in increases in FEV1 between the two groups and no difference in as-needed use of medication.

We also observed an interesting phenomenon among AHEAD participants which indicated that at times of increasingly poor asthma control, SMART provided added protection from exacerbations compared with high-dose salmeterol/fluticasone plus SABA. This observation suggests that SMART may be particularly beneficial in patients who have either suboptimal asthma control, more active disease or who are exposed to more asthma triggers. The cost of treating patients with the SMART strategy was also 24% lower in Canada compared with the other regimen (P<0.001).

Corroborative Findings from COSMOS

An earlier study again validated the SMART strategy vs. salmeterol/fluticasone. The COSMOS study (Vogelmeier et al. Eur Respir J 2005;26:819-28) randomized 2143 adolescents and adults to either the SMART strategy (160/4.5 µg in two inhalations b.i.d. plus as-needed inhalations) or to salmeterol/fluticasone 50/250 µg b.i.d. plus salbutamol as needed, for a treatment interval of 12 months. The study was an open-label design, thus enabling physicians to up-titrate or down-titrate maintenance doses of either combination, depending on the patient’s needs.

At the end of 12 months, the risk of patients experiencing a severe exacerbation was 25% lower in the SMART arm vs. the comparator arm. The total rate of severe exacerbations was also 22% lower with maintenance plus as-needed budesonide/formoterol vs. salmeterol/fluticasone while the overall burden of exacerbations was reduced by SMART as follows: a 36% reduction in the total number of days with severe exacerbations of any time duration; a 24% reduction in unscheduled visits; a 34% reduction in oral steroid days due to severe exacerbations; a 16% reduction in ER visits; and a 37% reduction in hospital days. Improved asthma control as observed in the SMART arm was not achieved as a result of patients over-relying on their as-needed medications, as the use of as-needed medication was 38% lower throughout the study compared with the alternative arm.

Guiding Asthma Management

Several clinically relevant observations may be made based on findings that emerged from our own study and others that may be helpful in guiding asthma management.

AHEAD showed that patients often rely quite heavily on reliever medications and over-use is often associated with imminent exacerbation. Many recommend that the ICS dose be doubled in the face of an imminent exacerbation, but several studies have shown that this strategy is not always effective.

In one study by Harrison et al. (Lancet 2004; 363:271-5), for example, doubling the dose of the ICS once peak flow or symptoms deteriorated did little to improve asthma control and did not reduce the need for oral steroid treatment. Rabe et al. (Chest 2006; 129:246-56) also reported that the incidence of severe exacerbations was lower among patients receiving low-dose ICS combined with a LABA for both maintenance and relief compared with a higher maintenance dose of budesonide plus a SABA for relief.

It may be preferable to increase the dose of an ICS more than twice the baseline dose at the onset of an exacerbation, as it should be specified on the patient’s action plan, but for those using budesonide/formoterol, the use of this medication as both maintenance and symptom relief may overcome the problem of undertreating asthma during periods of poor asthma control, if only because patients are exposed to more anti-inflammatory medication each time they seek relief from symptoms.

Assess Patients for Triggers

Once the diagnosis of asthma has been made, it is not enough to simply initiate treatment based on disease severity and health care use. Physicians also need to assess patients for individual triggers to the disease—notably, smoking and environmental exposure at work—and test patients for comorbid conditions as well as allergies. Patient education is also critical for good asthma control, ideally initiated by the physician and reinforced by an asthma educator.

Wherever possible, treatment should be simplified to improve adherence. Patients also need to understand how the medication works to relieve their symptoms and reduce exacerbations, and that a decline in asthma control is largely the result of poor management. Physicians therefore need to emphasize the importance of adherence and assess patient adherence to the regimen so as to alleviate any concerns they may have.

Adequate environmental control is also critical for good asthma control. Patients need to understand, for example, that domestic allergens can precipitate a deterioration in asthma control while smoking contributes both to a decline in control and a reduction in the efficacy of ICS therapy, a double indemnity that makes smoking cessation a major target in the management of upper airway disease.

The latest Canadian guidelines did not yet recommend the use of budesonide/formoterol as maintenance and reliever therapy for the treatment of asthma that is greater than mild in severity. Nevertheless, the logic of this strategy has been accepted by at least some organizations, including the Global Initiative for Asthma (GINA) guidelines. Global consensus also indicates that other expert groups consider these recommendations to be appropriate, given the weight of evidence supporting the merits of the SMART strategy. Indeed, most asthma experts already consider the SMART option when making a decision as to which regimen may be best suited to an individual patient.

I am thus persuaded that Canadian guidelines will reflect current practice once formally published, as pivotal studies to date indicate that the SMART strategy is a valid treatment option which may improve asthma control and help prevent severe asthma exacerbations in many patients.

Note: In Canada, budesonide/formoterol is approved for use in 100 ug/6 ug, 200 ug/6 ug and 400 ug/12 ug formats.