M E Howitt, Family Physician, Carlton Clinic, Black Rock, St Michael, Barbados, President of the Caribbean Allergy and Respiratory Association (CARA), and Medical Adviser to the Asthma Association of Barbados

Despite extensive research, there have not been any significant drug developments in the treatment of asthma in recent years. However, the discovery that inhaled corticosteroids and long-acting b2-agonists have complimentary and synergic effects has led to a change in the treatment paradigm for asthma. There is now overwhelming evidence that the addition of a long-acting b2-agonist to an inhaled corticosteroid gives better control in patients with mild to moderate persistent asthma, as measured by reduced symptoms, improved lung function and reduced exacerbations. This combination therapy is now being used effectively in the management of both asthma and chronic obstructive pulmonary disease.

Introduction
Asthma is a chronic disease with episodes of exacerbation; the underlying pathophysiology is characterized by airway inflammation, smooth muscle dysfunction and airway remodelling. The smooth muscle dysfunction involves bronchial hyperresponsiveness, exaggerated bronchial smooth muscle constriction and hyperplasia of the smooth muscle cells of the airways. The underlying acute and chronic inflammation is characterized by the recruitment and activation of a number of inflammatory cells such as dendritic cells, mast cells, eosinophils and CD4+ lymphocytes, and the release of a number of mediators such as cytokines that establish and perpetuate both the underlying inflammation and the muscosal oedema and epithelial damage seen in asthma. Tissue damage and repair result in the deposition of interstitial collagen in the lamina reticulosa of the basement membrane below the epithelium. This thickening of the basement membrane, together with alterations in the epithelium, blood vessels, goblet cells and smooth muscle, is referred to as airway remodelling.
The understanding that asthma is a chronic dynamic disease involving airway inflammation, smooth muscle dysfunction and remodelling has led to changes in the treatment paradigms for this disease. The goal of asthma treatment is to achieve control of the disease and prevent exacerbations. To achieve optimal control of asthma it is logical to use therapies that are targeted at the underlying pathophysiological processes: airways inflammation and smooth muscle dysfunction. The two therapies that are most effective in targeting these components are inhaled corticosteroids and long-acting b2-agonists. It is the combination of these two old drugs and the understanding of the synergy between them that has led the way in the modern management of asthma, rather than the development of any new types of drugs.

Inhaled corticosteroids
Inhaled corticosteroids remain the most effective type of drug currently available for the treatment of asthma. They benefit patients with chronic persistent asthma by decreasing airway inflammation, reducing bronchial hyperresponsiveness, improving lung function, reducing exacerbations, decreasing the need for oral cortico­steroids and reducing mortality, and may also prevent airway remodelling and alter the natural history of the disease. No other drug is as effective for the treatment of the underlying pathology of this disease. Inhaled corticosteroids are recommended in the Caribbean Guidelines on the Management of Asthma as the first-line treatment for all patients with persistent asthma. These guidelines recommend a dose range of 200-1000 mg/day for fluticasone propionate and 800-2000 mg/day for budesonide or beclomethasone in moderate persistent asthma. However, several studies have shown that much lower doses may be adequate. Holt et al.1 examined the dose–response relationship of fluticasone in adolescents and adults with asthma; eight studies involving 2324 patients were included in this meta-analysis. The main outcome measures were forced expiratory volume in 1 second (FEV1), morning and evening peak expiratory flow rates, nocturnal awakening, b2-agonist use and major exacerbations. The dose–response curve began to plateau at 100-200 mg/day and peaked at 500 mg/day. These doses produced 90% of the benefit of 1000 mg/day. In the Asthma Clinical Research Network study,2 low and medium doses of inhaled corticosteroids were also shown to be adequate. A near-maximal FEV1 increase occurred with low dose fluticasone (88 mg/day) and medium dose beclomethasone (672 mg/day). High doses (704 mg/day of fluticasone or 1344 mg of beclomethasone) did not increase the FEV1 or the provocative concentration that produces a 20% fall in FEV1, but did increase systemic side effects. In effect, because of the flat dose–response curve, near-maximum benefit from inhaled corticosteroids is achieved at relatively low to medium doses. Any small increase in benefit at high doses is obtained at the expense of a disproportionate increase in side effects.
However, low and medium doses of inhaled corticosteroids are not adequate to control all asthmatics. The addition of a second drug to a low or medium maintenance dose of inhaled corticosteroid would make therapeutic sense. It has become clear that long-acting b2-agonists fit this add-on role perfectly, and this provides the rationale for the development of the combination therapy approach to the treatment of asthma.

Long-acting b2-agonists
The introduction of inhaled long-acting b2-agonists to the asthma therapeutic armamentarium turned out to be a major development. Studies have shown that salmeterol and formoterol produce a sustained improvement in pulmonary function that persists for more than 12 hours. Compared with regularly administered, short-acting b2-agonists and placebo, the long-acting b2-agonists were superior for all parameters, including pulmonary function and the number of night-time and daytime asthma symptoms.
When asked to help with the introduction of salmeterol in the Caribbean in the early 1990s, I was initially concerned about their safety. Since they were not primarily anti-inflammatory in action, it was thought that they would mask the underlying inflammation of asthma and trigger more severe exacerbations. There was concern that they would cause downregulation of the b2 receptors with chronic use and blunt the response to short-acting b2-agonists when used as a rescue medication. There was also uncertainty about when to use these drugs and where they would fit into the asthma treatment regimen. Several studies have established that, in the clinical setting, there is no reduction in the response to an inhaled short-acting b2-agonist taken to relieve symptoms in patients taking regular long-acting b2-agonists.3 It has also been shown there is a decrease in exacerbations when a long-acting b2-agonist is added to a low dose inhaled corticosteroid compared with doubling the dose of the inhaled steroid.

Because long-acting b2-agonists lack consistent anti-inflammatory activity, they are not recommended for use as a monotherapy.

Combination therapy
It is not surprising that long-acting b2-agonists and inhaled corticosteroids should have complimentary effects: the two classes of drugs have very different modes of action and target different aspects of the disease process. Long-acting b2-agonists target smooth muscle dysfunction and inhaled corticosteroids target the underlying inflammation. They have been shown to interact at the molecular level, where their actions appear to be synergic. However, the major development occurred when it was shown that, for all outcomes measured, the addition of a long-acting b2-agonist to an inhaled corticosteroid was superior to doubling the dose of inhaled corticosteroid.

The two landmark studies of Greening et al.4 and Woolcock et al.5 were the first to investigate the effects of adding an inhaled long-acting b2-agonist to an inhaled corticosteroid when the asthma was not controlled by the corticosteroid. Greening et al.4 studied 429 patients with mild to moderate asthma who were symptomatic despite treatment with 200 mg beclomethasone twice daily. The subjects were randomized to receive either a 2.5-fold higher dose of inhaled beclomethasone or 200 mg of beclomethasone plus 50 mg of salmeterol for 6 months. The addition of salmeterol produced significantly better symptom and peak flow improvement than increasing the dose of inhaled corticosteroid. The study by Woolcock et al.5 showed essentially the same thing: adding salmeterol had a more rapid and pronounced beneficial effect on symptoms than doubling the dose of inhaled corticosteroid.

These studies firmly established the position of inhaled long-acting b2-agonists as add-on therapy when the maintenance dose of inhaled corticosteroids is not controlling the asthma. Furthermore, studies have shown that long-acting b2-agonists are superior to theophylline or the leukotriene receptor antagonists as an add-on medication.

There were concerns about the safety of adding a long-acting b2-agonist to a fixed dose of inhaled corticosteroid, as it was thought that, since the drug did not have any significant anti-inflammatory properties, it would not control the underlying inflammation and might mask the progression of inflammation and worsen exacerbations. The Formoterol and Corticosteroids Establishing Therapy (FACET) study carried out by Pauwels et al.6 was specifically designed to investigate whether the addition of regular treatment with the long-acting b2-agonist formoterol to regular low or higher dose therapy with budesonide would result in improved control of asthma symptoms and lung function without any long-term deterioration in asthma control over a 12-month period. The primary outcome variables were severe and mild exacerbations. Although the single most successful strategy for reducing major exacerbations of asthma was a quadrupling of the dose of budesonide from 200 mg/day to 800 mg/day, the results showed that the addition of formoterol to budesonide led to improved lung function, decreased night-time awakening and decreased use of rescue medication. More importantly, there was a significant reduction in the number of both mild and severe exacerbations, which are better measurements of control of the underlying airway inflammation than lung function. Severe exacerbations were decreased by 25%. This reduction in the rate of asthma exacerbation by the addition of a long-acting b2-agonist to an inhaled corticosteroid was confirmed by the Optimal Treatment of Mild Asthma (OPTIMA) study,7 in which the addition of formoterol to 200 mg of budesonide was more effective at preventing exacerbations than 400 mg of budesonide alone. Analysis of the exacerbation data further showed that not only was the rate of exacerbations reduced, but the mean duration of the exacerbations was reduced from 10.5 to 8.4 days, confirming the superiority of combination therapy.

Studies in children have shown that the addition of an inhaled long-acting b2-agonist is of value from the age of 5 years when the asthma is insufficiently controlled despite a low to moderate dose of inhaled corticosteroid.

Scientific rationale for combination therapy
The combination of long-acting b2-agonists and inhaled corticosteroids is logical as these drugs have complimentary actions on different areas of the underlying complex pathophysiology of asthma and are thought to enhance each other at the molecular level.8 Inhaled corticosteroids inhibit many aspects of the chronic inflammatory process and may reverse several of the processes involved in airway remodelling, whereas long-acting b2-agonists have effects on airway smooth muscle and may attenuate components of acute inflammation. In addition, the combination of inhaled corticosteroids and long-acting b2-agonists has greater efficacy than the combination of inhaled cortico­steroids with theophylline or leukotriene receptor antagonists. This would suggest that there is some complimentary interaction between inhaled corticosteroids and long-acting b2-agonists at the molecular level. Several studies support this hypothesis. Corticosteroids may regulate b2-receptor function by increasing expression of the receptor, restoring G protein/b2-receptor coupling and inhibiting b2-receptor downregulation. Long-acting b2-agonists may prime the glucocorticoid receptor. These molecular and receptor mechanisms may be responsible for the additive and synergic effects of the drugs on the inflammatory process underlying asthma. This is reflected in the enhanced anti-inflammatory activity with combination therapy, which is greater than that with either drug alone, and the potential steroid-sparing effects seen with long-acting b2-agonists.

Asthma control
Despite many years of research, we still do not fully understand the natural history of asthma or its exacerbations and we cannot prevent or cure this disease. However, we do have a large number of drugs that are effective and relatively free from side effects with which to treat the disease, and achieve asthma control. The aims of asthma control are:

• minimal (ideally no) chronic symptoms, including nocturnal symptoms
• minimal (infrequent) episodes of exacerbations
• no emergency visits
• minimal need for quick-relief b2-agonists
• no limitation of activities, including exercise
• peak expiratory flow variability <20%
• (near) normal peak expiratory flow rate
• minimal or no adverse effects from medications.

The Gaining Optimal Asthma Control (GOAL) study9 compared inhaled corticosteroid fluticasone with a combination of fluticasone and the long-acting b2-agonist salmeterol in 3421 patients with uncontrolled asthma. The inhaled fluticasone component of the treatment was increased at 3 month intervals until total control was achieved or the subject was receiving a maximum of 500 mg of fluticasone propionate twice daily. Significantly more patients in each of the three strata (previously corticosteroid-free or previously taking low or moderate doses of corticosteroids) achieved control with the fluticasone–salmeterol combination than with fluticasone alone. After 1 year, total control was achieved by 28% compared with 41% and well-controlled status by 59% compared with 71% in those receiving fluticasone alone and those receiving the fluticasone–salmeterol combination, respectively. Combination therapy appears to be superior to inhaled corticosteroid alone in achieving control of asthma and at a lower total dose of inhaled corticosteroid, although some patients require relatively high doses of the combination therapy to achieve control.

Combination treatment for both maintenance and relief
Fomotorol has a rapid onset of action with a long bronchodilator effect and has been shown to be effective as a reliever medication in asthma, with systemic side effects of a similar duration to a short-acting b2-agonist.10 In a recent study involving over 2500 patients,11 a combined formoterol/ budesonide inhaler was used as maintenance therapy twice daily, and additional puffs were used as needed for symptom relief. This regimen was compared with the same maintenance dose and with a four-fold greater dose of budesonide alone, both with the short-acting b2-agonist terbutaline as needed. Use of the combination inhaler for both maintenance and relief significantly reduced the number of severe exacerbations over the 1 year treatment period compared with other treatments; it also reduced the need for oral corticosteroids and improved asthma control and lung function compared with the other treatment regimens.
The use of a single combination inhaler for both maintenance and rescue would simplify treatment management plans and is likely to increase compliance. It is probably what occurs in daily practice anyway, with medication use being increased when there is an increase in symptoms. On the surface, this approach would appear to be more pharmacologically expensive, but it could in fact be cost-effective since it would decrease the number of exacerbations, resulting in fewer visits to the emergency department or asthma bay and decreasing the number of hospital admissions.
The role of combination therapy in the Caribbean Guidelines for the Management and Prevention of Asthma
The Caribbean Guidelines for the Management and Prevention of Asthma were drawn up at a meeting in Trinidad in July 1997 organized by the Caribbean Health Research Council (CHRC) and the Global Initiative for Asthma (GINA). The guidelines were a response to the wide variation in the treatment of asthma across the Caribbean12,13 and attempted to provide a unified and evidence-based approach to the management of asthma in this area. A second meeting was held in Trinidad in April 2003 to update the Guidelines; the emphasis of this second meeting was on patient education and self-management plans.
The Guidelines adopted a stepwise approach to achieve asthma control (Table 1), aiming to abolish symptoms as soon as possible and optimize peak flow. Patients should be started on therapy at a level appropriate to the severity of their asthma. The aim is to achieve control early and maintain control by stepping up treatment as necessary and stepping down treatment when the control is good.
Based on Step 2 (mild persistent) and Step 3 (moderate persistent) of the Guidelines, a long-acting b2-agonist should be added to a low to medium maintenance dose of inhaled corticosteroid if the asthma is not well controlled on the inhaled cortico­steroid alone (Figure 1). The alternative is to double the dose of the inhaled corticosteroid but these drugs have a flat dose–response curve and, as the studies cited above have shown, adding a long-acting b2-agonist is more effective.

Single inhaler versus separate inhalers for combination therapy
Combination therapy could be given in the form of two separate inhalers or, if available, as a combination inhaler. The scientific rationale for co-administration of an inhaled cortico­steroid and a long-acting b2-agonist in a single inhaler rather than two separate inhalers is that for optimal interaction the two drugs must reach the same target cells together in adequate concentrations. Nelson et al.14 performed a meta-analysis of four clinical studies comparing combination therapy with fluticasone and salmeterol with the concurrent use of the individual components administered separately at the same doses. They showed that there was a clear and consistent trend in favour of combination therapy over concurrent therapy. An additional 5-14% of patients treated with combination therapy achieved a greater than 30 l/minute improvement in morning peak expiratory flow compared with those treated with concurrent therapy. Similarly, a greater than 15 l/minute improvement was achieved in an extra 7-9% of patients receiving combination versus concurrent therapy. It was thought that these results are due to enhanced synergy of fluticasone and salmeterol caused by codeposition in the airways after administration with a single inhaler.

Conclusions
Asthma remains one of the most common chronic conditions seen in children and adults in the Caribbean and is associated with an unacceptable high morbidity. As the natural history of the disease and the causes of exacerbations are not fully understood, we cannot practice primary or secondary prevention. Despite the availability of highly effective therapies, there is still considerable failure to control the symptoms of asthma and exacerbations of the disease, as seen by the large number of repeat visits to hospital emergency departments. The introduction of combination therapy for the management of asthma has changed the paradigm for the treatment of this disease. Combination inhalers are more convenient to use and have been shown to be more effective than the concurrent use of the two drugs, and asthma control is achieved at lower doses of inhaled corticosteroids. Combination inhalers also ensure that the corticosteroid is not discontinued. They are cost-effective as they decrease exacerbations and possible hospital admissions. In the countries of the Caribbean where combination inhalers are not available, combination therapy using concurrent inhalers is still very effective but compliance should be stressed and monitored.

References
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