- Email: [email protected]
Formoterol—where does it fit in the current guidelines?
Vol.95 (2001)(SUPPLEMENT B), S30-$34
Formoterol
IIl~l~ll~lm~lllD][lll~l~r-~
where does it fit in the current
guidelines? R. PAUWELS Department of Respiratory Diseases, University Hospital Ghent, Belgium
Drugs availabletotreat asthma have improved considerably over the pastthree decades and understanding of the disease process is continually improving. However, the incidence of asthma is increasing and the cause(s) of this increase are not yet identified. Asthma is often underdiagnosed and undertreated. Poor compliance with medication is also an important consideration in how effective management strategies can be. The aim of current asthma treatment, according to the Global Initiative for Asthma (GINA), is to control the disease. However, two surveys, one in Europe and the other in the U.S.A. indicate that the objectives of treatment guidelines are not being met. Patients were shown to experience high rates of exacerbations and require many doses of reliever medication.There was also a large difference between patient and physician perceptions of treatment--this needs to be countered b/improved education for both the general public and healthcare professionals. Fo:moterol, which is the only/~2-agonist to possess both fast- and longacting properties, may help to improve patient compliance by allowing a single inhaler to be used for both maintenance and as-needed therapy. However, although formote:ol is already widely used as maintenance therap)4, currenttreatment guidelines do not include the use of formoterol as first-line reliever medication. Evidence is increasing to support asneeded use and a large, randomized effectiveness stud), in 18000 patients across the world is ongoing to assessthe safety and efficacy offormoterol as needed in a real-life setting.The results from the Real-Life Effectiveness of Oxis®Turbuha let ® (RELIEF)study should help to establish the position of formoterol as an effective fi rst-line reliever medication and ultimately lead to the inclusion offormoterol as needed in treatment guidelines. Abstract
© 2001Harcourt PublishersLtd doi:10.1053/rmed.2001.1144.
iili!
INTRODUCTION Understanding of the pathophysiology of asthma is improving all the time and more is now known about the underlying inflammatory processes that result in symptoms and acute attacks. Although treatment of asthma has advanced over the past 30 years due to the availability of drugs to treat symptoms (e.g. short-acting/32-agonists) and inflammation (e.g. inhaled corticosteroids), the prevalence of asthma has increased over the past two decades (I,2). Allergen exposure and parental smoking have both been identified as risk factors but the impact of air pollution has not been proven. The Global Initiative for Asthma (GINA) is a project conducted in collaboration with the National Heart, Lung and Blood Institute and the World Health Organization with the aim of helping healthcare professionals to reduce asthma prevalence, morbidity and mortality. Correspondence should be addressedto: R. Pauwels,Departmentof Respiratory Diseases,University Hospital, De Pintelaan185,9000 Ghent, Belgium.Fax:(+32) 9 2402341; E-mail: [email protected]
¸ i Although GINA produces guidelines for asthma diagnosis and treatment, it is also important not to forget patient needs in working towards the optimum treatment strategy Patients are not so concerned with clinical measures such as peak flow measurements or forced expiratory volume in I second (FEVi)--for patients, the main aim is to have a treatment strategy that allows them to live normal lives with minimum interference in everyday activities. The GINA treatment guidelines are currently being updated, and any changes to current guidelines will be based on strong evidence of efficacy, safety, comparison with other therapies and cost-effectiveness. As it has now been suggested that many meta-analyses have serious methodological flaws, it may be better for such evidence to be obtained from large randomized studies (3). Currently, short-acting/~2-agonists are placed as reliever medication for symptom control. In contrast, fl2-agonists with long-acting properties, formoterol and salmeterol, are recommended only as maintenance therapy in moderate to severe patients poorly controlled on inhaled corticosteroids. Formoterol differs from all
FORNOTEROL--CURRENT GUIDELINES
other #2-agonists, including salmeterol--it has not only a long duration of action but also a fast onset, and is therefore suitable for use as needed as well as in regular therapy.
G I N A GUIDELINES FOR T H E TREAT M E N T OF A S T H M A The GINA guidelines state that the goal of asthma therapy should be to" eliminate all symptoms, including those experienced at night-time; prevent exacerbations and minimize need for as-needed #2-agonist therapy; prevent limitation of activities; minimize side effects from treatment; and provide the patient with near normal lung function (4). However, asthma prevalence is increasing, particularly in children, and it is often underdiagnosed and undertreated. Treatment guidelines stress the importance of controlling inflammation, in particular with inhaled corticosteroids, and emphasis is placed on gaining control of symptoms promptly and stepping down treatment when control has been achieved. The
$31
use of long-acting #2-agonists with low-dose inhaled corticosteroids is an effective alternative to increasing the dose of corticosteroids prescribed for patients with moderate persistent asthma (5). The Asthma Insights and Reality in Europe (AIRE) study was a large survey carried out in seven countries across Europe (6). Over 2800 asthmatic adults and children were questioned about their asthma status and treatment. Current asthma (defined as physician diagnosed with symptoms within the last 12 months) was found to be prevalent in 3488 out of 73 880 households screened. When patients were questioned about their disease management, it was clear that treatment of asthma in Europe falls well short of the goals for long-term management established by GINA. Over one-third of children and half of all the adults surveyed had daytime symptoms at least once per week and only 39.5% of children and 55% of adults reported ever having had a lung function test performed by their doctor. Other findings are summarized inTable I.
RESPIRATORYMEDICINE
S32
Patients were classified as having mild intermittent, mild persistent, moderate persistent or severe persistent asthma according to the frequency and severity of symptoms reported. When questioned about their disease control, patients felt that their asthma was well managed and 76.5% of children and 65.9% of adults said they had either no symptoms or mild asthma during the past 4 weeks. However, some of the patients who felt that their disease was either well- or completely-controlled were actually assessed as having severe persistent asthma (Fig. I). Many factors were felt to contribute to the difference between patient perception and the reality of asthma control. Not only do patients underestimate the severity of their disease, they also overestimate the degree to which their asthma is controlled. Patients, thus, accept a lower degree of control than is achievable with current treatment strategies. Furthermore, this is compounded by physicians, as many trust the patients'own perception of their disease state and do not monitor the condition closely by adequate history taking and performing regular lung function tests. A similar survey in the U.S.A.--Asthma in America (AIA)~cluestioned over 2500 adults and children and found similar results (7). Patients were poorly controlled, with many exacerbations and a high level of lost work or school days. Sleep disruption, due to breathing problems at least once per week, was reported by 30% of patients and 48% said that asthma limits their ability to take part in sports or recreation. Other results are summarized inTable 2. Even though comprehensive treatment guidelines are available, many patients and their families suffer to an unnecessary degree due to morbidity associated with their asthma. Additionally, 47% of patients used their reliever medication daily, including 74% of patients with severe persistent and 21% with mild intermittent asthma. According to the guidelines, this level
:::::::::::::::::::::: :[:::1"-Io{ mitations o~ ac~Mties :[~
100 75
lUlUU
Iil
:::::a Well/completely controlled mz]~Somewhat controlled . m Poorly/not controlled
50 25
SP
MOP MP Children
MI
SP
MOP
MI
100 75 w.
•~
50 25
MP
Adults
Figure I. Symptom severity index by patient/parent classification of asthma control (6), Symptom severity index according to frequency and severity of symptoms, SP: severe persistent; HOP: moderate persistent; HP: mild persistent; lv]l: mild intermittent, [Repr-oduced with permission from
Eur Respirj~
of short-acting flz-agonist use is an indicator of poorly controlled asthma. These surveys signify the importance of better education for asthmatic patients and their primary care physicians. Without this, optimal treatment cannot be achieved and the objectives of the GINA treatment guidelines will not be met. Future initiatives by GINA include the supervision of World Asthma Day activities and development of an asthma practice audit and information gateway, with the aim of increasing
:::::A7%:ofpati~nts:us~drelieve~medicatibndAily :: :::it:::::
::
FORHOTEROL--CURRENT GUIDELINES
$33
Formoterol Turbuhaler®4.5 gg as needed
patient awareness of their disease and, thus, improving treatment.
F O R M O T E R O L m P O S I T I O N IN C U R R E N T A N D F U T U R E GUIDELINES Formoterol is widely accepted to have a unique position as the only fl2-agonist with both fast- and long-acting properties. In current guidelines, fl2-agonists with a long-acting profile, including formoterol, are first-choice therapies for combination with low-to-moderate dose inhaled corticosteroids in moderate to severe asthma; data have shown this to be an effective choice, which is well tolerated in patients (5). Formoterol is also currently used as add-on therapy to high-dose corticosteroids in patients with severe persistent asthma--in combination with other drugs--and can decrease the need for oral steroids by reducing the number of exacerbations (8). Although formoterol is licensed in many countries for as-needed therapy in patients already receiving it as maintenance therapy, it is not currently included as firstline reliever medication in management guidelines. However, evidence is increasing to support the use of formoterol in this and other areas of asthma treatment, including as-needed use in exercise-induced bronchoconstriction (EIB) and also for regular use in mild persistent asthma in addition to low doses of inhaled corticosteroids. In the Oxis 'g~ and Pulmicort ~ Turbuhaler 'g' in the Management of Asthma (OPTIMA) study the addition of formoterol 4.5 #g twice daily to budesonide resulted in fewer severe exacerbations and poorly controlled days in patients insufficiently controlled on budesonide 100 Itg twice daily compared with increasing the dose of budesonide to 200#g twice daily (9). Formoterol 4.5 #g has been shown to provide more effective control, compared with terbutaline 500 itg, when used as first-line reliever medication in mild to moderate persistent asthma on maintenance therapy with inhaled corticosteroids (10). Additionally, in patients with moderate to severe persistent asthma on regular treatment with the combination of inhaled corticosteroids and long-acting inhaled fl2-agonists, formoterol has been shown to be as good as terbutaline when used as needed (11). In patients receiving regular twice-daily treatment with formoterol plus additional inhalations as needed, superior asthma control was shown in patients with moderate to severe asthma compared with salbutamol, twice daily plus as needed (12). Furthermore, formoterol has been shown to be well tolerated, with side effects similar in nature and duration to other fl2-agonists (13-16). In EIB, a number of studies have shown that formoterol produces a degree of bronchoprotection equivalent to terbutaline, but with a much longer duration (17-18).
q
Salbutamol pMD1200 gg as needed (or equivalent dose via DPI)
Randomization Number of months 0
1
L A~I Visit number 1
] 2
3
6
13
14
I Telephonecontact
Figure 2. RELIEFstudy design, pP1DI: pressurized metered dose inhaler; DPI: dry powder inhaler.
Although with continued use it is not clear whether the maximum duration of effect, i.e. 12 h, is maintained, formoterol does still provide significant protection, even after prolonged use. Health economics is also very important in deciding which treatment strategy is the most appropriate. Adding formoterol to inhaled corticosteroid therapy has been shown to be a cost-effective approach in the treatment of moderately asthmatic patients (19). Furthermore, in the Tattersfield study (10) formoterol used as first-line reliever medication has been shown to generate cost savings compared with terbutaline, resulting from a decrease in the number of severe exacerbations experienced (20). The available evidence supports the use of formoterol as needed in all types and severities of asthma.There is a suggestion that, as well as improving asthma control, it could also result in a decrease in healthcare utilization. This hypothesis has still to be tested in large studies reflecting true clinical practice. Many studies, with very specific inclusion and exclusion criteria, limit the type of patients included and it is not always possible to extrapolate the results observed to the general population. The Real-Life Effectiveness of Oxis c~ Turbuhaler ~' (RELIEF) study is an ongoing trial designed to present a comprehensive picture of formoterol used as needed. This large, open, randomized, parallel-group study in 18 000 patients across the world includes a broad range of patients and assesses the use of formoterol as needed in asthmatic patients over a 6-month period. Patients 6 years or older, with a diagnosis of asthma, and requiring fl2-agonist therapy for relief of symptoms, were randomized to receive their usual maintenance treatment plus either formoterol 4.5#g or salbutamol 200#g, both as needed. Patients with concurrent conditions, other than pregnancy or lactation, will be included.The study design is shown in Fig. 2.
$34
T h e study aims t o d e t e r m i n e t h e t h e r a p e u t i c o u t c o m e w i t h f o r m o t e r o l as needed in a real clinical s e t t i n g and p a t i e n t p o p u l a t i o n , i.e. t h e effectiveness o f f o r m o t e r o l as first-~ine reliever m e d i c a t i o n . T h e p r i m a r y clinical o b j e c t i v e is t o assess t h e safety o f f o r m o t e r o l as needed by m o n i t o r i n g serious adverse events and discontinuations o f t h e r a p y due t o adverse events. T h e s e c o n d a r y objective is t o c o m p a r e t h e efficacy o f f o r m o t e r o l w i t h salbut a m o l by m o n i t o r i n g t i m e t o f i r s t e x a c e r b a t i o n , w h i c h is defined as h o s p i t a l i z a t i o n due t o d e t e r i o r a t i n g asthma, e m e r g e n c y t r e a t m e n t due t o asthma, a r e q u i r e m e n t f o r o r a l steroids lasting at least 5 days o r a need t o increase m a i n t e n a n c e t h e r a p y due t o w o r s e n i n g asthma. O t h e r efficacy p a r a m e t e r s t o be c o l l e c t e d are: n u m b e r o f exacerbations; use o f as-needed m e d i c a t i o n ; and n u m b e r o f days w i t h asthma. T h e study w i l l also include data on health e c o n o m i c s including h e a l t h c a r e resource utilizat i o n and t h e n u m b e r o f days patients are incapable o f c o n d u c t i n g t h e i r usual activities.
CONCLUSIONS C u r r e n t l y available data suggest t h a t f o r m o t e r o l is an effective and w e l l - t o l e r a t e d t r e a t m e n t o p t i o n in patients w i t h asthma, in b o t h as-needed and regular t r e a t m e n t . T h e RELIEF study should help t o establish t h e place of f o r m o t e r o l in a s t h m a m a n a g e m e n t , u l t i m a t e l y leading t o t h e inclusion o f f o r m o t e r o l in t r e a t m e n t guidelines f o r use as needed in all patients w i t h asthma. F o r m o t e r o l has been s h o w n t o be effective in a s t h m a o f all severities and w i t h its fast o n s e t and long d u r a t i o n o f action p r o vides additional benefits c o m p a r e d w i t h o t h e r /~2agonists. It is w e l l t o l e r a t e d in high doses and suitable f o r use in mildly a s t h m a t i c patients and in t h e t r e a t m e n t o f acute attacks. F u r t h e r m o r e , f o r patients r e q u i r i n g b o t h m a i n t e n a n c e and reliever therapy, f o r m o t e r o l could be used in b o t h circumstances, r e d u c i n g t h e n u m b e r o f inhalers necessary whilst maintaining good asthma control.
REFERENCES I. Sears MR. Epidemiological trends in asthma. Can Respir J 1996; 3: 261-268. 2. LangeP, Parner J,VestboJ, Schnohr P,Jensen G. A 15-year follow-up study of ventilatory function in adults with asthma. N Engl j Med 1998; 339: 1194-1200. 3. JadadAR, Moher M, Browman GPeta/. Systemic reviews and metaanalyses on treatment of asthma: critical evaluation. BMJ 2000; 320: 537-540. 4. Global Initiative for Asthma. Pocket guide for asthma management and prevention.Washington: National Heart, Lung and Blood Institute, 1998.
RESPIRATORY M E D I C I N E
5. Pauwels RA, L~fdahl C-G, Postma DS et al. Effect of inhaled formoterol and budesonide on exacerbations of asthma. Formoterol and Corticosteroids EstablishingTherapy (FACET) International Study Group. N Eng/j Med 1997;337: 1405-1411. 6. Rabe KF,Vermeire PA, SorianoJB, Maier WC. Clinical management in asthma in 1999:the Asthma Insights and Reality in Europe (AIRE) study. Eur Respir} 2000; 16: 802-807. 7. Rickard KA, Stempel DA. Asthma survey demonstrates that the goals of the NHLBI have not been accomplished.} Allergy C/in Imrnu no/1999; 103 (Part 2, No. I): $655. 8. H~icki MA, Hinz GW, Medici TC. Clinical experience over five years of daily therapy with formoterol in patients with bronchial asthma. Clin Drug Invest 1997; 14: 165-174. 9. Barnes PJ,O'Byrne PM, Rodriguez-Roisin R et al. From the Oxis and Pulmicort Turbuhaler In the Management of Asthma (OPTIMA) international study group. Treatment of mild persistent asthma with low doses of inhaled budesonide alone or in combination with formoterol. Thorax 2000; 55 (Suppl. 3)" $5. 10. Tattersfield A, L~fdahl CG, Postma DS et al. As needed medication in asthma: randomised trial comparing formoterol, a short acting ~-agonist with terbutaline. Lancet 2001; 357: 257-261. II. Ind P, B~sz~rmenyi Nagy G, Pietinalho A, Shiner R, Villasante C. Formoterol 4.511g, used as needed viaTurbuhaler was as safe and as well tolerated as terbutaline 0.5 mg. Eu~ Respirj 1999; 14 (Suppl. 30): 148S. 12. Wallin A, Mellander B, Rosenhall L, Sanstr~mT, W~hlander L. Formoterol, a new long-acting beta2-agonist for inhalation twice daily, compared with salbutamol in the treatment of asthma.Th0~ 1990; 45" 259-261. 13. T~tterman KJ, Huhti L, Sutinen E et al. Tolerability to high doses of formoterol and terbutaline via Turbuhaler '~ for 3 clays in stable asthmatic patients. Eur Respirj 1998; 12: 573-579. 14. Malolepszy J, B~sz~rmenyi Nagy G, Brander R, Larsson P. Formoterol 90/~g viaTurbuhaler was safe in patients with acute bronchoconstriction. Eur Respirj 1998; 12 (Suppl. 28): 323S. 15. Rosenborg J, BengtssonT, Larsson P, Blomgren A, Persson G, L~tvail J. Relative systemic dose potency and tolerability of inhaled formoterol and salbutamol in healthy subjects and asthmatics. Eurj Clin Pharmacol 2000; 56: 363-370. 16. Rott Z, B~cskei C, Poczi Metal. Formoterol (Oxis'~) Turbuhaler '~ has a more favorable therapeutic index ratio than salbutamol pMDI in asthma. Am Respir Crit Care Med 2001; 163 (no. 5, pt 2): A. 590. 17. Vilsvik J, Ankerst J, Palmqvist Met a/. Protection against cold air and exercise induced bronchoconstriction while on regular treatment with Oxis '~=.Respir Med 2001; 95: 484-490. 18. Gr6nner6d TA, von Berg A, Schwabe G, Soliman S. Formoterol vs Turbuhaler gave better protection than terbutaline against repeated exercise challenge for up to 12 hours in children and adolescents. RespirMed 2000; 94: 661-667. 19. Andersson F, St~hl E, Barnes PJeta/. For the Formoterol and Corticosteroids Establishing Therapy (FACET) International Study Group. Adding formoterol to budesonide in moderate asthmahealth economic results from the FACET study. Respir Med 2001; 95: 505-512. 20. Berggren F, Ekstr~m T, Gunzenhauser D. Formoterol was more cost-effective in a modelling study than terbutaline in as needed treatment of patients with moderate asthma. Eur Respirj 1999; 14 (Suppl. 30): 341s.
Formoterol
IIl~l~ll~lm~lllD][lll~l~r-~
where does it fit in the current
guidelines? R. PAUWELS Department of Respiratory Diseases, University Hospital Ghent, Belgium
Drugs availabletotreat asthma have improved considerably over the pastthree decades and understanding of the disease process is continually improving. However, the incidence of asthma is increasing and the cause(s) of this increase are not yet identified. Asthma is often underdiagnosed and undertreated. Poor compliance with medication is also an important consideration in how effective management strategies can be. The aim of current asthma treatment, according to the Global Initiative for Asthma (GINA), is to control the disease. However, two surveys, one in Europe and the other in the U.S.A. indicate that the objectives of treatment guidelines are not being met. Patients were shown to experience high rates of exacerbations and require many doses of reliever medication.There was also a large difference between patient and physician perceptions of treatment--this needs to be countered b/improved education for both the general public and healthcare professionals. Fo:moterol, which is the only/~2-agonist to possess both fast- and longacting properties, may help to improve patient compliance by allowing a single inhaler to be used for both maintenance and as-needed therapy. However, although formote:ol is already widely used as maintenance therap)4, currenttreatment guidelines do not include the use of formoterol as first-line reliever medication. Evidence is increasing to support asneeded use and a large, randomized effectiveness stud), in 18000 patients across the world is ongoing to assessthe safety and efficacy offormoterol as needed in a real-life setting.The results from the Real-Life Effectiveness of Oxis®Turbuha let ® (RELIEF)study should help to establish the position of formoterol as an effective fi rst-line reliever medication and ultimately lead to the inclusion offormoterol as needed in treatment guidelines. Abstract
© 2001Harcourt PublishersLtd doi:10.1053/rmed.2001.1144.
iili!
INTRODUCTION Understanding of the pathophysiology of asthma is improving all the time and more is now known about the underlying inflammatory processes that result in symptoms and acute attacks. Although treatment of asthma has advanced over the past 30 years due to the availability of drugs to treat symptoms (e.g. short-acting/32-agonists) and inflammation (e.g. inhaled corticosteroids), the prevalence of asthma has increased over the past two decades (I,2). Allergen exposure and parental smoking have both been identified as risk factors but the impact of air pollution has not been proven. The Global Initiative for Asthma (GINA) is a project conducted in collaboration with the National Heart, Lung and Blood Institute and the World Health Organization with the aim of helping healthcare professionals to reduce asthma prevalence, morbidity and mortality. Correspondence should be addressedto: R. Pauwels,Departmentof Respiratory Diseases,University Hospital, De Pintelaan185,9000 Ghent, Belgium.Fax:(+32) 9 2402341; E-mail: [email protected]
¸ i Although GINA produces guidelines for asthma diagnosis and treatment, it is also important not to forget patient needs in working towards the optimum treatment strategy Patients are not so concerned with clinical measures such as peak flow measurements or forced expiratory volume in I second (FEVi)--for patients, the main aim is to have a treatment strategy that allows them to live normal lives with minimum interference in everyday activities. The GINA treatment guidelines are currently being updated, and any changes to current guidelines will be based on strong evidence of efficacy, safety, comparison with other therapies and cost-effectiveness. As it has now been suggested that many meta-analyses have serious methodological flaws, it may be better for such evidence to be obtained from large randomized studies (3). Currently, short-acting/~2-agonists are placed as reliever medication for symptom control. In contrast, fl2-agonists with long-acting properties, formoterol and salmeterol, are recommended only as maintenance therapy in moderate to severe patients poorly controlled on inhaled corticosteroids. Formoterol differs from all
FORNOTEROL--CURRENT GUIDELINES
other #2-agonists, including salmeterol--it has not only a long duration of action but also a fast onset, and is therefore suitable for use as needed as well as in regular therapy.
G I N A GUIDELINES FOR T H E TREAT M E N T OF A S T H M A The GINA guidelines state that the goal of asthma therapy should be to" eliminate all symptoms, including those experienced at night-time; prevent exacerbations and minimize need for as-needed #2-agonist therapy; prevent limitation of activities; minimize side effects from treatment; and provide the patient with near normal lung function (4). However, asthma prevalence is increasing, particularly in children, and it is often underdiagnosed and undertreated. Treatment guidelines stress the importance of controlling inflammation, in particular with inhaled corticosteroids, and emphasis is placed on gaining control of symptoms promptly and stepping down treatment when control has been achieved. The
$31
use of long-acting #2-agonists with low-dose inhaled corticosteroids is an effective alternative to increasing the dose of corticosteroids prescribed for patients with moderate persistent asthma (5). The Asthma Insights and Reality in Europe (AIRE) study was a large survey carried out in seven countries across Europe (6). Over 2800 asthmatic adults and children were questioned about their asthma status and treatment. Current asthma (defined as physician diagnosed with symptoms within the last 12 months) was found to be prevalent in 3488 out of 73 880 households screened. When patients were questioned about their disease management, it was clear that treatment of asthma in Europe falls well short of the goals for long-term management established by GINA. Over one-third of children and half of all the adults surveyed had daytime symptoms at least once per week and only 39.5% of children and 55% of adults reported ever having had a lung function test performed by their doctor. Other findings are summarized inTable I.
RESPIRATORYMEDICINE
S32
Patients were classified as having mild intermittent, mild persistent, moderate persistent or severe persistent asthma according to the frequency and severity of symptoms reported. When questioned about their disease control, patients felt that their asthma was well managed and 76.5% of children and 65.9% of adults said they had either no symptoms or mild asthma during the past 4 weeks. However, some of the patients who felt that their disease was either well- or completely-controlled were actually assessed as having severe persistent asthma (Fig. I). Many factors were felt to contribute to the difference between patient perception and the reality of asthma control. Not only do patients underestimate the severity of their disease, they also overestimate the degree to which their asthma is controlled. Patients, thus, accept a lower degree of control than is achievable with current treatment strategies. Furthermore, this is compounded by physicians, as many trust the patients'own perception of their disease state and do not monitor the condition closely by adequate history taking and performing regular lung function tests. A similar survey in the U.S.A.--Asthma in America (AIA)~cluestioned over 2500 adults and children and found similar results (7). Patients were poorly controlled, with many exacerbations and a high level of lost work or school days. Sleep disruption, due to breathing problems at least once per week, was reported by 30% of patients and 48% said that asthma limits their ability to take part in sports or recreation. Other results are summarized inTable 2. Even though comprehensive treatment guidelines are available, many patients and their families suffer to an unnecessary degree due to morbidity associated with their asthma. Additionally, 47% of patients used their reliever medication daily, including 74% of patients with severe persistent and 21% with mild intermittent asthma. According to the guidelines, this level
:::::::::::::::::::::: :[:::1"-Io{ mitations o~ ac~Mties :[~
100 75
lUlUU
Iil
:::::a Well/completely controlled mz]~Somewhat controlled . m Poorly/not controlled
50 25
SP
MOP MP Children
MI
SP
MOP
MI
100 75 w.
•~
50 25
MP
Adults
Figure I. Symptom severity index by patient/parent classification of asthma control (6), Symptom severity index according to frequency and severity of symptoms, SP: severe persistent; HOP: moderate persistent; HP: mild persistent; lv]l: mild intermittent, [Repr-oduced with permission from
Eur Respirj~
of short-acting flz-agonist use is an indicator of poorly controlled asthma. These surveys signify the importance of better education for asthmatic patients and their primary care physicians. Without this, optimal treatment cannot be achieved and the objectives of the GINA treatment guidelines will not be met. Future initiatives by GINA include the supervision of World Asthma Day activities and development of an asthma practice audit and information gateway, with the aim of increasing
:::::A7%:ofpati~nts:us~drelieve~medicatibndAily :: :::it:::::
::
FORHOTEROL--CURRENT GUIDELINES
$33
Formoterol Turbuhaler®4.5 gg as needed
patient awareness of their disease and, thus, improving treatment.
F O R M O T E R O L m P O S I T I O N IN C U R R E N T A N D F U T U R E GUIDELINES Formoterol is widely accepted to have a unique position as the only fl2-agonist with both fast- and long-acting properties. In current guidelines, fl2-agonists with a long-acting profile, including formoterol, are first-choice therapies for combination with low-to-moderate dose inhaled corticosteroids in moderate to severe asthma; data have shown this to be an effective choice, which is well tolerated in patients (5). Formoterol is also currently used as add-on therapy to high-dose corticosteroids in patients with severe persistent asthma--in combination with other drugs--and can decrease the need for oral steroids by reducing the number of exacerbations (8). Although formoterol is licensed in many countries for as-needed therapy in patients already receiving it as maintenance therapy, it is not currently included as firstline reliever medication in management guidelines. However, evidence is increasing to support the use of formoterol in this and other areas of asthma treatment, including as-needed use in exercise-induced bronchoconstriction (EIB) and also for regular use in mild persistent asthma in addition to low doses of inhaled corticosteroids. In the Oxis 'g~ and Pulmicort ~ Turbuhaler 'g' in the Management of Asthma (OPTIMA) study the addition of formoterol 4.5 #g twice daily to budesonide resulted in fewer severe exacerbations and poorly controlled days in patients insufficiently controlled on budesonide 100 Itg twice daily compared with increasing the dose of budesonide to 200#g twice daily (9). Formoterol 4.5 #g has been shown to provide more effective control, compared with terbutaline 500 itg, when used as first-line reliever medication in mild to moderate persistent asthma on maintenance therapy with inhaled corticosteroids (10). Additionally, in patients with moderate to severe persistent asthma on regular treatment with the combination of inhaled corticosteroids and long-acting inhaled fl2-agonists, formoterol has been shown to be as good as terbutaline when used as needed (11). In patients receiving regular twice-daily treatment with formoterol plus additional inhalations as needed, superior asthma control was shown in patients with moderate to severe asthma compared with salbutamol, twice daily plus as needed (12). Furthermore, formoterol has been shown to be well tolerated, with side effects similar in nature and duration to other fl2-agonists (13-16). In EIB, a number of studies have shown that formoterol produces a degree of bronchoprotection equivalent to terbutaline, but with a much longer duration (17-18).
q
Salbutamol pMD1200 gg as needed (or equivalent dose via DPI)
Randomization Number of months 0
1
L A~I Visit number 1
] 2
3
6
13
14
I Telephonecontact
Figure 2. RELIEFstudy design, pP1DI: pressurized metered dose inhaler; DPI: dry powder inhaler.
Although with continued use it is not clear whether the maximum duration of effect, i.e. 12 h, is maintained, formoterol does still provide significant protection, even after prolonged use. Health economics is also very important in deciding which treatment strategy is the most appropriate. Adding formoterol to inhaled corticosteroid therapy has been shown to be a cost-effective approach in the treatment of moderately asthmatic patients (19). Furthermore, in the Tattersfield study (10) formoterol used as first-line reliever medication has been shown to generate cost savings compared with terbutaline, resulting from a decrease in the number of severe exacerbations experienced (20). The available evidence supports the use of formoterol as needed in all types and severities of asthma.There is a suggestion that, as well as improving asthma control, it could also result in a decrease in healthcare utilization. This hypothesis has still to be tested in large studies reflecting true clinical practice. Many studies, with very specific inclusion and exclusion criteria, limit the type of patients included and it is not always possible to extrapolate the results observed to the general population. The Real-Life Effectiveness of Oxis c~ Turbuhaler ~' (RELIEF) study is an ongoing trial designed to present a comprehensive picture of formoterol used as needed. This large, open, randomized, parallel-group study in 18 000 patients across the world includes a broad range of patients and assesses the use of formoterol as needed in asthmatic patients over a 6-month period. Patients 6 years or older, with a diagnosis of asthma, and requiring fl2-agonist therapy for relief of symptoms, were randomized to receive their usual maintenance treatment plus either formoterol 4.5#g or salbutamol 200#g, both as needed. Patients with concurrent conditions, other than pregnancy or lactation, will be included.The study design is shown in Fig. 2.
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T h e study aims t o d e t e r m i n e t h e t h e r a p e u t i c o u t c o m e w i t h f o r m o t e r o l as needed in a real clinical s e t t i n g and p a t i e n t p o p u l a t i o n , i.e. t h e effectiveness o f f o r m o t e r o l as first-~ine reliever m e d i c a t i o n . T h e p r i m a r y clinical o b j e c t i v e is t o assess t h e safety o f f o r m o t e r o l as needed by m o n i t o r i n g serious adverse events and discontinuations o f t h e r a p y due t o adverse events. T h e s e c o n d a r y objective is t o c o m p a r e t h e efficacy o f f o r m o t e r o l w i t h salbut a m o l by m o n i t o r i n g t i m e t o f i r s t e x a c e r b a t i o n , w h i c h is defined as h o s p i t a l i z a t i o n due t o d e t e r i o r a t i n g asthma, e m e r g e n c y t r e a t m e n t due t o asthma, a r e q u i r e m e n t f o r o r a l steroids lasting at least 5 days o r a need t o increase m a i n t e n a n c e t h e r a p y due t o w o r s e n i n g asthma. O t h e r efficacy p a r a m e t e r s t o be c o l l e c t e d are: n u m b e r o f exacerbations; use o f as-needed m e d i c a t i o n ; and n u m b e r o f days w i t h asthma. T h e study w i l l also include data on health e c o n o m i c s including h e a l t h c a r e resource utilizat i o n and t h e n u m b e r o f days patients are incapable o f c o n d u c t i n g t h e i r usual activities.
CONCLUSIONS C u r r e n t l y available data suggest t h a t f o r m o t e r o l is an effective and w e l l - t o l e r a t e d t r e a t m e n t o p t i o n in patients w i t h asthma, in b o t h as-needed and regular t r e a t m e n t . T h e RELIEF study should help t o establish t h e place of f o r m o t e r o l in a s t h m a m a n a g e m e n t , u l t i m a t e l y leading t o t h e inclusion o f f o r m o t e r o l in t r e a t m e n t guidelines f o r use as needed in all patients w i t h asthma. F o r m o t e r o l has been s h o w n t o be effective in a s t h m a o f all severities and w i t h its fast o n s e t and long d u r a t i o n o f action p r o vides additional benefits c o m p a r e d w i t h o t h e r /~2agonists. It is w e l l t o l e r a t e d in high doses and suitable f o r use in mildly a s t h m a t i c patients and in t h e t r e a t m e n t o f acute attacks. F u r t h e r m o r e , f o r patients r e q u i r i n g b o t h m a i n t e n a n c e and reliever therapy, f o r m o t e r o l could be used in b o t h circumstances, r e d u c i n g t h e n u m b e r o f inhalers necessary whilst maintaining good asthma control.
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RESPIRATORY M E D I C I N E
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