Combination Therapy with Inhaled Long-Acting
`b2-Agonists and Inhaled Corticosteroids:
`A Paradigm Shift in Asthma Management
`
`Stuart Stoloff, M.D., Kim Poinsett-Holmes, Pharm.D., and Paul M. Dorinsky, M.D.
`Long-acting inhaled b2-agonists and inhaled corticosteroids are classes of
`drugs with different mechanisms of action that are commonly used to provide
`effective long-term control of persistent asthma. Scientific and clinical data
`support the complementary mechanisms of action of the inhaled
`corticosteroids and the long-acting b2-agonists in achieving a superior level of
`asthma control. In addition, evidence supports significant reductions in
`exacerbations and effective control of airway inflammation with an inhaled
`corticosteroid and a long-acting b2-agonist versus higher dosages of inhaled
`corticosteroids or combinations of other therapeutic agents with an inhaled
`corticosteroid. Finally, there are distinct economic advantages to combining
`an inhaled corticosteroid and a long-acting b2-agonist in the treatment of
`asthma relative to other treatment regimens.
`(Pharmacotherapy 2002;22(2):212–226)
`
`OUTLINE
`
`Scientific Rationale
`Clinical Rationale
`Control of Inflammation
`Adding a Long-Acting b2-Agonist versus Other
`Regimens
`Inhaled Corticosteroid with a Long-Acting b2-Agonist
`Efficacy
`Safety
`Quality of Life
`Clinical Issues
`Adherence to Treatment Plan
`Cost-Effectiveness
`Summary
`
`Asthma, a chronic airway disease, affects
`approximately 17.3 million people in the United
`States.1 It is associated with significant morbidity
`and mortality. Approximately 5000 deaths are
`attributed to asthma each year. 2 Asthma
`From the University of Nevada School of Medicine, Reno,
`Nevada (Dr. Stoloff); and GlaxoSmithKline Inc., Research
`Triangle Park, North Carolina (Drs. Poinsett-Holmes and
`Dorinsky).
`Address reprint requests to Stuart Stoloff, M.D., 1200
`North Mountain Street, Suite 220, Carson City, NV 89703.
`
`accounts for an estimated total health care cost of
`$11 billion each year and an annual loss of more
`than 3 million work days and 10 million school
`days.3–5
`Adult-onset asthma frequently is encountered
`in primary care and has been reported to occur in
`over 10%, and potentially as high as 17%, of the
`primary care patient population.6 However,
`asthma generally is underdiagnosed in the
`primary care setting.7 Underdiagnosis of asthma
`by general practitioners may be a result of
`physicians’ lack of awareness of the morbidity
`experienced by these patients. 8 Given the
`morbidity and mortality associated with asthma
`and its prevalence in the primary care community,
`clinicians must prescribe therapy that is effective
`and directed to the major pathophysiologic
`alterations associated with this disease.
`Asthma is a disease of two components:
`inflammation and bronchoconstriction (Figure
`1). It is a complex disease involving many
`airway cells and mediators. To our knowledge,
`no single treatment regimen exists to effectively
`treat both the underlying inflammation and the
`bronchoconstriction. Thus, pharmacotherapy for
`Exhibit 1020
`IPR2017-00807
`ARGENTUM
`
`000001
`
`

`

`COMBINATION THERAPY IN ASTHMA MANAGEMENT Stoloff et al
`
`213
`
`the leukotriene modifiers.29–34 Both the inhaled
`corticosteroids and the long-acting b2-agonists
`are quite effective in the treatment of persistent
`asthma; however, these two classes of drugs have
`different mechanisms of action.
`Corticosteroids prevent the formation of both
`prostaglandins (cyclooxgenase pathway) and
`leukotrienes (5-lipoxygenase pathway) from
`arachadonic acid. Inhaled corticosteroids also
`inhibit multiple airway inflammatory cells that
`may be involved in the asthma response.35
`Corticosteroids modulate the action of numerous
`inter- and intracellular mediators and influence
`the transcription of target genes that regulate the
`production of cytokines, receptors, and enzymes.
`The long-acting b2-agonists bind to the b2-
`adrenoceptor, thereby stimulating the production
`of cyclic adenosine 3¢ ,5¢ -monophosphate and
`
`asthma has focused on treating both components
`of the disease individually. Consequently, the
`drugs administered most frequently to treat
`asthma are those that promote bronchodilatation
`and those that reduce inflammation.
`As the complexity of a drug regimen increases,
`poor adherence to a treatment plan is likely to
`occur.9, 10 The impact of poor adherence to
`treatment is poor control of the underlying
`inflammation and bronchoconstriction, which,
`on a long-term basis, could contribute to the
`development of severe asthma exacerbations and
`possibly to irreversible damage to the lungs—a
`process known as airway remodeling.11–19 Even
`widespread educational programs and promotion
`of national treatment guidelines have not
`overcome problems associated with suboptimal
`adherence to treatment regimens, which often
`include more than one controller agent.20–22
`Clearly, new approaches to the long-term
`treatment of asthma are needed.
`
`Scientific Rationale
`Inhaled corticosteroids are more potent and
`effective in controlling airway inflammation than
`any of the other available long-term controllers
`(e.g., nedocromil, cromolyn, leukotriene
`modifiers).23–28 Similarly, the long-acting b2-
`agonist bronchodilators have been shown to
`improve pulmonary function and reverse
`bronchoconstriction better than the short-acting
`b2-agonists (e.g., albuterol), theophylline, and
`
`Smooth
`muscle
`dysfunction
`
`Airway
`inflammation
`
`• Bronchoconstriction
`• Bronchial hyperreactivity
`• Hyperplasia and hypertrophy
`• Inflammatory mediator
`release
`
`• Inflammatory cell
`infiltration and activation
`• Mucosal edema
`• Cellular proliferation
`• Epithelial damage
`• Basement membrane
` thickening
`
`Symptoms, exacerbations, and
` lung scarring
` (airway remodeling)
`
`Figure 1. The dual components of asthma.
`
`Figure 2. In vitro evidence suggests that b2-agonists may
`prime inactive corticosteroid receptors (2A) and that
`corticosteroids may increase the number of b2-receptors and
`their sensitivity to b2-agonists (2B). Primed receptors are
`activated more easily by corticosteroids, and less steroid is
`required to convert the primed receptor to an active
`receptor. This priming effect could explain why a lower
`dosage of an inhaled corticosteroid plus a long-acting b2-
`agonist is more effective than a higher dosage of an inhaled
`corticosteroid alone.
`
`000002
`
`

`

`214
`
`PHARMACOTHERAPY Volume 22, Number 2, 2002
`
`causing relaxation of bronchial smooth muscle
`and inhibition of the release of proinflammatory
`mediators (in vitro) from mast cells.36
`When used concurrently, these two classes of
`drugs have complementary effects on each other
`(Figure 2).37–43 Inhaled corticosteroids have been
`shown to upregulate b2-receptor expression. In
`human lung, corticosteroids increased b2-
`adrenergic receptor transcription.38 Corticosteroids
`also induce b2-receptor messenger RNA
`transcription and improve b2-receptor function
`in human airway epithelial and glandular cells
`(in vivo and in vitro).40 Likewise, long-acting b2-
`agonists enhance the effects of corticosteroids, a
`process that may occur through priming of the
`glucocorticoid receptor for activation. 41
`In
`support of this concept, the long-acting b2-
`agonist, salmeterol, enhances steroid-induced
`inhibition of cell proliferation and inflammatory
`mediator release, and it enhances steroid-induced
`eosinophil apoptosis.39, 42 Recently, the authors of
`one study43 reported a synergistic increase in the
`inhibitory effects of inhaled corticosteroids on
`tumor necrosis factor-a–stimulated interleukin-8
`release by salmeterol in cultured human airway
`smooth muscle cells.
`The exact role that these complementary
`actions play in producing the clinical benefits
`associated with the use of both an inhaled
`corticosteroid and a long-acting b2-agonist in
`patients with asthma is not completely defined.
`However, these data do suggest that, besides their
`different mechanisms of action in asthma,
`inhaled corticosteroids may confer benefits to the
`effectiveness of long-acting b2-agonists and vice
`versa.36
`
`Clinical Rationale
`
`Control of Inflammation
`
`Effect on Exacerbations
`
`Exacerbations are regarded as a practical
`marker for overall disease control and control of
`the underlying pathophysiology of asthma.
`Thus, exacerbation rates are an excellent
`indicator of whether or not a drug regimen is
`effective. Some investigators have suggested that
`long-term treatment with long-acting b2-agonists
`might result in tolerance or mask an increase in
`airway inflammation, thus leading to an increase
`in exacerbations or more severe exacerbations.44
`The results of several studies indicate that the
`addition of a long-acting b2-agonist to an inhaled
`corticosteroid in patients with symptoms does
`
`not increase the frequency of exacerbations.45–49
`By contrast, the combination of these two classes
`of drugs more effectively reduces asthma
`exacerbations than do higher doses of an inhaled
`corticosteroid alone.45–49 Table 1 summarizes the
`details of these studies, as well as the studies
`described in the following sections.
`One group of authors45 performed a meta-
`analysis on nine studies that evaluated the
`efficacy of adding salmeterol versus doubling the
`dose of inhaled corticosteroid in patients aged 12
`years or older who were symptomatic while
`receiving an inhaled corticosteroid at a minimum
`dosage of 200 µg/day. The total number of
`exacerbations and the number of moderate and
`severe exacerbations were reduced significantly
`by adding salmeterol to a low dosage of an
`inhaled corticosteroid (as defined by the National
`Heart, Lung, and Blood Institute guidelines12)
`compared with a higher dosage of an inhaled
`corticosteroid alone (Figure 3).
`The Formoterol and Corticosteroids
`Establishing Therapy (FACET) study examined
`the effect of adding the long-acting b2-agonist
`formoterol 12 µg twice/day to either low-dosage
`(200 µg/day) or high-dosage (800 µg/day)
`budesonide in 852 patients with asthma who
`were previously symptomatic but had been
`stabilized over 4 weeks while receiving
`budesonide 1600 µg/day. 46 After 1 year of
`treatment, the rate of severe exacerbations was
`reduced by 63% with the combination of
`formoterol and the higher dosage of budesonide,
`by 49% with the higher dosage of budesonide
`alone, and by 26% with formoterol and the lower
`dosage of budesonide. At both the low and high
`dosages of budesonide, adding formoterol
`resulted in greater reductions in severe and mild
`exacerbations compared with those of inhaled
`corticosteroid alone.
`To evaluate whether or not treatment with a
`long-acting b2-agonist might mask the symptoms
`of an impending exacerbation, another group of
`authors 49 analyzed the changes in peak
`expiratory flow (PEF) and asthma symptoms
`during the 2 weeks before and after the 425
`severe exacerbations that occurred during the
`FACET study. The exacerbations that occurred
`in patients taking formoterol did not differ in
`severity or in response to treatment compared
`with exacerbations in patients not taking
`formoterol (i.e., no statistical significance).
`There was no difference in the ability of patients
`to recognize deteriorating asthma, regardless of
`formoterol use.
`
`000003
`
`

`

`COMBINATION THERAPY IN ASTHMA MANAGEMENT Stoloff et al
`
`215
`
`Table 1. Studies Describing Treatment with a Long-Acting b2-Agonist and an Inhaled Corticosteroid
`Previous
`Age Range
`Drug Regimen
`Treatment
`Treatment
`(yrs)
`(no. of pts)
`Duration
`
`Results
`
`SL > ZL, p≤0.001;
`AM PEF: 29.6 vs 13.0 L/min;
`symptom-free days: 22.4% vs
`8.8%; FEV1: NS
`SL > ML, p<0.001;
`AM PEF: 35.0 vs 21.7 L/min;
`symptom-free days: 24% vs
`16%; FEV1: NS
`FP + SL > FP + ML, p≤0.032;
`AM PEF: 24.9 vs 13.0 L/min;
`FEV1: 0.34 vs 0.20 L;
`% days without albuterol:
`26.3% vs 19.1%
`ICS + SL > ICS + ZL, p<0.001;
`AM PEF: 28.8 vs 13.0 L/min;
`symptom-free days: 20% vs
`9%; FEV1: NS
`
`SL > › dosage of ICS, p≤0.02;
`AM PEF difference: 27.7 L/min;
`FEV1 difference: 0.08 L;
`% symptom-free days: 15%;
`exacerbation difference: 2.73%
`BD + FM > higher-dosage BD,
`p≤0.01; fl
`severe exacerbation:
`63% vs 49%; daytime symptom
`score: 0.33 vs 0.53
`
`Pattern of change in PEF,
`symptoms, and rescue drugs
`were similar in all groups,
`indicating no negative effect
`of formoterol on severity and
`duration of exacerbations
`
`Combination > SL, FP, or
`placebo, p≤0.036; change in
`FEV1: 0.48 L vs 0.05, 0.25,
`-0.11 L; change in AM PEF:
`53.5 L/min vs -11.6, 15.2,
`-14 L/min; % symptom-free
`days: 33.8% vs 2.1%, 15.4%,
`-7.9%
`Combination > SL, FP, or
`placebo, p≤0.025; change in
`FEV1: 0.51 L vs 0.11, 0.28,
`0.01 L; change in AM PEF:
`52.5 L/min vs -1.7, 17.3, -23.7
`L/min; % symptom-free days:
`22.6% vs 8.0%, 7.2%, -3.8%
`
`Study Design
`Add long-acting
`b2-agonists vs
`leukotriene modifiers
`R, DB, PG32
`ICS in 80%
`of patients
`
`12–73
`
`SL 42 µg MDI (144)
`ZL 20 mg b.i.d. (145)
`
`4 wks
`
`R, DB, PG33
`
`ICS
`
`15–83
`
`R, DB, PG34
`
`ICS
`
`15–83
`
`Retrospective
`analysis of
`2 R, DB,
`PG studies69
`
`Add salmeterol vs
`› dosage inhaled
`corticosteroids
`Meta-analysis
`of 9 R, DB,
`PG trials45
`
`ICS
`
`‡ 12
`
`ICS 200–
`1600 µg/day
`
`‡ 12
`
`R, DB, PG46
`
`ICS
`
`18–70
`
`ICS
`
`18–70
`
`Retrospective
`analysis of
`425 severe
`exacerbations49
`
`Combined vs
`individual agents
`R, DB, PG47
`
`ICS
`
`12–69
`
`R, DB, PG48
`
`ICS or SL
`only
`
`12–70
`
`SL 50 µg powder b.i.d.
`(476)
`ML 10 mg q.d. (472)
`
`FP 100 µg + SL 50 µg
`powder b.i.d. (222)
`FP 100 µg + ML 10 mg q.d.
`(225)
`
`SL 42 µg b.i.d.
`ZL 20 mg b.i.d.
`(429 total)
`
`12 wks
`
`12 wks
`
`4 wks
`
`12–26 wks
`
`12 mo
`
`12 mo
`
`› dosage of ICS
`400–2000 µg/day
`SL 42 or 50 µg b.i.d.
`(3685 total)
`
`BD 100 µg b.i.d. (213)
`BD 100 µg + FM 12 µg
`b.i.d. (210)
`BD 400 µg b.i.d. (214)
`BD 400 µg + FM 12 µg
`b.i.d. (215)
`BD 100 µg b.i.d. (213)
`BD 100 µg + FM 12 µg
`b.i.d. (210)
`BD 400 µg b.i.d. (214)
`BD 400 µg + FM 12 µg
`b.i.d. (215)
`
`12 wks
`
`SL 50 µg + FP 250 µg
`combination powder b.i.d.
`(84)
`SL 50 µg b.i.d. (88)
`FP 250 µg b.i.d. (84)
`Placebo (93)
`
`12 wks
`
`SL 50 µg + FP 100 µg
`combination powder b.i.d.
`(92)
`SL 50 µg b.i.d. (92)
`FP 100 µg b.i.d. (90)
`Placebo (82)
`
`000004
`
`

`

`Study Design
`Effect of salmeterol
`on inflammation
`R, DB, PG,
`biopsy50
`
`ICS
`
`42 (mean)
`
`ICS
`
`20–70
`
`R, DB, PG,
`biopsy,
`bronchoalveolar
`lavage51
`
`Concurrent vs individual
`and higher-dosage
`inhaled corticosteroids
`R, DB, PG70
`Short-acting
`b-agonists
`only
`
`12–61
`
`216
`
`PHARMACOTHERAPY Volume 22, Number 2, 2002
`
`Table 1. Studies Describing Treatment with a Long-Acting b2-Agonist and an Inhaled Corticosteroid (continued)
`Previous
`Age Range
`Drug Regimen
`Treatment
`Treatment
`(yrs)
`(no. of pts)
`Duration
`
`Results
`
`12 wks
`
`12 wks
`
`FP 200 µg b.i.d. (19)
`FP 500 µg b.i.d. (19)
`FP 200 µg + SL 50 µg
`b.i.d. (18)
`
`SL 50 µg powder b.i.d.
`(13)
`FP 100 µg powder b.i.d.
`(16)
`Placebo (16)
`
`FP + SL caused a fl
`in
`submucosal mast cells vs FP
`200 µg (p<0.05); no worsening
`of airway inflammation with
`addition of SL
`No deterioration in airway
`inflammation; fl
`in EGI-
`positive (activated) eosinophils
`from 18.3 to 7.6 cells/mm with
`SL + ICS (p=0.01)
`
`4 wks
`
`SL 42 µg + FP 88 µg b.i.d.
`(25)
`SL 42 µg + FP 220 µg b.i.d.
`(21)
`FP 220 µg b.i.d. (23)
`FP 88 µg b.i.d. (23)
`SL 42 µg b.i.d. (21)
`Placebo (23)
`
`FP + SL > FP, SL, or placebo,
`p<0.05; change in FEV1: 0.73
`and 0.59 L vs 0.30, 0.27, 0.29,
`0.09 L; change in AM PEF: 32
`and 57 L/min vs 25, 10, 41, -1.0
`L/min; % symptom-free days:
`FP + SL > FP and placebo
`groups only
`
`Add salmeterol vs
`› dosage budesonide,
`triamcinolone acetonide,
`or fluticasone propionate
`R, DB, PG71
`ICS
`
`36 (mean)
`
`SL 50 µg + FP 100 µg b.i.d. 12 wks
`(176)
`BD 400 µg b.i.d. (173)
`
`R, DB, PG72
`
`ICS
`
`14–80
`
`R, DB, PG73
`
`ICS
`
`12–79
`
`SL 50 µg + FP 250 µg b.i.d. 24 wks
`(180)
`BD 800 µg b.i.d. (173)
`
`FP 88 µg + SL 42 µg b.i.d.
`FP 220 µg b.i.d.
`TAA 600 µg b.i.d.
`(680 total)
`
`12 wks
`
`Combined vs
`concurrent therapy
`R, DB, PG74
`
`ICS
`
`12–79
`
`R, DB, PG75
`
`ICS
`
`13–75
`
`28 wks
`
`28 wks
`
`SL 50 µg + FP 500 µg
`combination powder b.i.d.
`(167)
`SL 50 µg + FP 500 µg
`concurrent inhalers b.i.d.
`(171)
`FP 500 µg b.i.d. (165)
`SL 50 µg + FP 250 µg
`combination powder b.i.d.
`(180)
`SL 50 µg + FP 250 µg
`concurrent powder
`inhalers b.i.d. (191)
`
`FP + SL > BD, p≤0.022;
`AM PEF: 426 vs 415 L/min;
`PM PEF: 435 vs 424 L/min;
`asthma symptoms: NS
`FP + SL > BD, p<0.05;
`FEV1: 2.53 vs 2.44 L;
`AM PEF: 406 vs 380 L/min;
`% symptom-free days increase:
`60% vs 34%
`FP + SL > FP and TAA, p<0.05;
`change in FEV1: 0.58 L vs 0.48
`and 0.34 L; change in AM PEF:
`58 L/min vs 47 and 18 L/min
`(p<0.05 for TAA only);
`% symptom-free days: 29.2%
`vs 22.6% and 11.9%(p<0.05
`for TAA only)
`
`Clinical equivalence with
`combination and concurrent
`treatment; increase in AM PEF:
`12% and 10%; combination >
`FP, p<0.001; change in AM
`PEF: 29 vs 9 L/min
`
`Clinical equivalence with
`combination and concurrent
`treatment; AM PEF: 43 and
`36 L/min
`
`000005
`
`

`

`COMBINATION THERAPY IN ASTHMA MANAGEMENT Stoloff et al
`
`217
`
`Study Design
`R, DB, PG76
`
`Results
`Clinical equivalence with
`combination and concurrent
`treatment; AM PEF: 42 and 33
`L/min
`
`Clinical equivalence with
`combination and concurrent
`treatment; AM PEF: 33 and 28
`L/min
`
`Table 1. Studies Describing Treatment with a Long-Acting b2-Agonist and an Inhaled Corticosteroid (continued)
`Previous
`Age Range
`Drug Regimen
`Treatment
`Treatment
`(yrs)
`(no. of pts)
`Duration
`ICS
`12–78
`SL 50 µg + FP 100 µg
`12 wks
`combination powder b.i.d.
`(121)
`SL 50 µg + FP 100 µg
`concurrent powder
`inhalers (123)
`SL 50 µg + FP 100 µg
`combination powder b.i.d.
`(125)
`SL 50 µg + FP 100 µg
`concurrent powder
`inhalers b.i.d. (132)
`R = randomized; DB = double-blind; PG = parallel group; ICS = inhaled corticosteroid; SL = salmeterol; MDI = metered-dose inhaler; ZL =
`zafirlukast; AM = morning; PEF = peak expiratory flow; FEV1 = forced expiratory volume in 1 second; NS = not significant; ML = montelukast;
`FP = fluticasone propionate; BD = budesonide; FM = formoterol; PM = evening; TAA = triamcinolone acetonide.
`
`R, DB, PG77
`
`ICS
`
`4–11
`
`12 wks
`
`In another study,48 the authors showed that in
`356 patients previously treated with low dosages
`of an inhaled corticosteroid or salmeterol, none
`of the patients treated for 12 weeks with the
`combination product (fluticasone propionate 100
`µg and salmeterol 50 µg twice/day) were
`withdrawn from the study owing to clinical
`exacerbations compared with withdrawal rates of
`16%, 6%, and 4% in patients treated with
`salmeterol, placebo, or fluticasone propionate
`alone, respectively. Another group47 reported
`similar results in 349 patients previously treated
`with medium dosages of an inhaled corticosteroid.
`
`In that 12-week study, fewer patients (2%)
`treated with the combination product (fluticasone
`propionate 250 µg and salmeterol 50 µg
`twice/day) were withdrawn from the study
`because of clinical exacerbations compared with
`patients treated with placebo (17%), salmeterol
`(12%), or fluticasone propionate (7%) alone.
`These results do not indicate that control of
`airway inflammation, as assessed by exacerbation
`rates, is compromised by the addition of a long-
`acting b2-agonist to the inhaled corticosteroid.
`In contrast, these data indicate that exacerbations
`are greatly reduced with combination treatment
`
`Figure 3. Difference in proportion of patients with one or more exacerbations (with 95% confidence intervals). Positive
`differences indicate treatment benefit with addition of salmeterol. (Adapted from reference 45 with permission.)
`
`000006
`
`

`

`218
`
`PHARMACOTHERAPY Volume 22, Number 2, 2002
`
`using two classes of drugs that have different
`modes of action, indicating a beneficial effect on
`overall asthma control.
`
`Control of Airway Inflammation
`
`Results of two bronchial biopsy and
`bronchoalveolar lavage studies indicate that the
`addition of a long-acting b2-agonist to inhalation
`corticosteroid therapy is at least as effective as
`higher dosages of an inhaled corticosteroid in
`controlling airway inflammation.50, 51
`In the first
`study,50 the effect of 12 weeks of treatment with
`fluticasone propionate 400 µg/day, with (18
`patients) or without (19 patients) salmeterol 50
`µg twice/day, and fluticasone propionate 1000
`µg/day (19 patients) on airway inflammation was
`evaluated in 56 patients who were symptomatic
`despite therapy with an inhaled corticosteroid.
`Bronchial biopsy results showed that compared
`with baseline and fluticasone propionate 400
`µg/day alone, the combination significantly
`reduced the number of airway mast cells. There
`was also a significant reduction from baseline in
`CD4+ cells in the combination group that was not
`seen with either dosage of fluticasone propionate
`alone.
`The second study51 evaluated the effect of 12
`weeks of supplementary treatment with placebo,
`salmeterol 50 µg twice/day, or fluticasone
`propionate 100 µg twice/day on airway
`inflammation in 45 patients with asthma who
`were symptomatic on low dosages of an inhaled
`corticosteroid. As in the first study,50 the results
`of the second study 51 showed that airway
`inflammation, as assessed by EGI-positive
`(activated) eosinophils in bronchial biopsy
`specimens, was at least as effectively controlled
`in patients treated with a low dosage of an
`inhaled corticosteroid and salmeterol compared
`with higher dosages of an inhaled corticosteroid
`alone. Thus, combination therapy with a long-
`acting b2-agonist and an inhaled corticosteroid
`may provide a level of control of airway
`inflammation that is as effective as that of higher
`dosages of an inhaled corticosteroid.
`
`Effect on Airway Remodeling
`
`Asthma is a chronic inflammatory process of
`the airways. By definition, any inflammatory
`process would involve repair and restoration of
`normal tissue structure and function, which
`could include replacement of injured tissue by
`connective tissue and its eventual maturation
`into scar tissue. In asthma, these processes and
`
`development of scar tissue in the airways may
`result in altered structure and function often
`referred to as remodeling of the airways (Figure
`1). These structural and functional changes can
`include thickening of the airway wall as a result
`of an increase in airway smooth muscle mass,
`increased vascularity, increases in mucous glands
`resulting in excessive mucus production,
`thickening of the reticular basement membrane,
`and increased collagen deposition.52
`Because inflammation is an early feature of
`asthma and is present even in patients with very
`mild or intermittent asthma, early initiation of an
`antiinflammatory treatment regimen may be
`necessary for the prevention of airway
`remodeling.11 Several studies have suggested that
`early intervention with an inhaled corticosteroid
`may prevent airway remodeling that results from
`inflammation.15, 17, 18 However, the effects of
`antiinflammatory drugs on the processes
`involved in airway remodeling are not com-
`pletely understood and require further study.52, 53
`
`Adding a Long-Acting b2-Agonist versus Other
`Regimens
`Clinicians frequently question what actions
`should be taken for a patient who is symptomatic
`while receiving inhaled corticosteroids: increase
`the dosage of the inhaled corticosteroid, add
`theophylline, add a leukotriene modifier, or add a
`long-acting b2-agonist. The following published
`data from clinical trials that specifically evaluated
`the long-acting b2-agonist therapy compared
`with other therapies suggest that the addition of
`a long-acting b2-agonist bronchodilator provides
`greater improvement in lung function and
`asthma symptom control than do the other
`therapeutic options.
`
`Increased Dosage of an Inhaled Corticosteroid
`A large and consistent body of published data
`from randomized, controlled clinical trials
`support the findings of statistically significant
`increases in efficacy with the addition of a long-
`acting b2-agonist compared with increasing the
`dosage of an inhaled corticosteroid in patients
`who are symptomatic on the corticosteroid.45, 46,
`54–63 These findings are true for all efficacy
`parameters studied (need for rescue albuterol,
`forced expiratory volume in 1 second [FEV1],
`PEF, symptoms, exacerbations) and are not
`dependent on the inhaled corticosteroid or
`inhaled long-acting b2-agonist administered.
`One group of authors45 performed a meta-
`
`000007
`
`

`

`COMBINATION THERAPY IN ASTHMA MANAGEMENT Stoloff et al
`
`219
`
`analysis based on nine parallel group trials of 12
`weeks or greater duration with 3685 patients
`(aged 12 years or older) who were symptomatic
`while receiving inhalation corticosteroid therapy.
`Patients in the studies were randomly assigned to
`treatment with salmeterol or an increased dosage
`(at least doubling) of their inhaled corticosteroid.
`The addition of salmeterol resulted in improved
`lung function and increased number of days and
`nights without symptoms or need for rescue
`treatment. More important, fewer patients
`experienced exacerbations with salmeterol
`compared with a higher dosage of an inhaled
`corticosteroid. These studies support the
`premise that asthma is a two-component disease
`and the treatment of both components is
`necessary for optimal control in most patients.
`
`Theophylline
`Several clinical trials compared the efficacy of a
`long-acting b2-agonist and theophylline in adult
`and adolescent patients, most of whom were
`previously treated with an inhaled corticosteroid.
`The results of these studies show that salmeterol
`42 µg twice/day was significantly more effective
`than theophylline in improving morning PEF,
`FEV1, and asthma symptoms and reducing
`nighttime awakenings and need for rescue
`albuterol after treatment for 2–12 weeks.64, 65 The
`authors of another study66 reported significant
`improvements with salmeterol inhalation powder
`50 µg twice/day in the median percentage of
`nights with no asthma symptoms and no need for
`rescue albuterol compared with dosage titration
`of slow-release theophylline; although, no
`significant differences were noted between
`treatment groups in PEF, symptoms, or need for
`rescue albuterol during the day.
`
`Leukotriene Modifiers
`Leukotriene modifiers are a relatively new class
`of drugs used to treat asthma. Three leukotriene
`modifiers—zafirlukast (Accolate; AstraZeneca
`Pharmaceuticals, Wilmington, DE), zileuton
`(Zyflo; Abbott Laboratories, Abbott Park, IL),
`and montelukast (Singulair; Merck & Co., Inc,
`Whitehouse Station, NJ)—are commercially
`available in the U.S. Leukotrienes are one of the
`many mediators implicated in asthma. They
`cause bronchoconstriction, mucus secretion,
`inflammatory cell infiltration, and increased
`microvascular permeability. By blocking the
`effects of leukotrienes or inhibiting their
`production, these drugs may decrease asthma
`
`symptoms and improve lung function. The
`current National Institutes of Health guidelines
`state that leukotriene modifiers may be
`considered an alternative to low-dosage inhaled
`corticosteroids for patients with mild persistent
`asthma. Although the results of a few studies
`show that the addition of a leukotriene modifier
`to an inhalation corticosteroid regimen may
`provide some clinical benefit,67, 68 leukotriene
`modifiers were shown to be less effective than
`inhaled corticosteroids in head-to-head studies,
`and, to our knowledge, no lung biopsy data exist
`to support significant antiinflammatory
`effects.26–28 Thus, their role as a controller in
`persistent asthma remains undefined.12
`
`Zafirlukast
`Two reports in the literature compared the
`efficacy of salmeterol 42 µg twice/day with that of
`zafirlukast 20 mg twice/day in symptomatic
`patients with asthma aged 12 years or older, most
`of whom were previously treated with an inhaled
`corticosteroid.32, 69 The first was a 4-week study
`with 299 patients in which the authors reported
`that salmeterol significantly improved morning
`and evening PEF, daytime asthma symptoms,
`nighttime asthma symptoms, percentage of
`symptom-free days, and percentage of days and
`nights with no need for rescue albuterol
`compared with zafirlukast.32
`In the other report, which included data from
`two studies (including the study just mentioned),
`a retrospective analysis in 429 patients previously
`treated with an inhaled corticosteroid revealed
`significantly greater improvements in morning
`PEF, percentage of symptom-free days, asthma
`symptom scores, and percentage of days with no
`need for rescue albuterol, as well as a significant
`reduction in the need for rescue albuterol,
`compared with zafirlukast.69
`These data indicate that the addition of a long-
`acting b2-agonist in patients symptomatic while
`receiving an inhaled corticosteroid provides
`significantly greater improvements in lung
`function and asthma symptom control than does
`the addition of a leukotriene modifier.
`
`Montelukast
`The authors of one study33 reported on the
`efficacy of salmeterol inhalation powder 50 µg
`twice/day compared with oral montelukast 10 mg
`once/day in a 12-week study with 948 patients
`aged 15 years or older who were symptomatic
`despite daily inhalation of a corticosteroid.
`
`000008
`
`

`

`220
`
`PHARMACOTHERAPY Volume 22, Number 2, 2002
`
`Patients treated with salmeterol had significantly
`greater improvements in morning and evening
`PEF, percentage of symptom-free days, percentage
`of rescue-free days, and overall daytime
`symptoms, compared with those taking
`montelukast.
`In another study,34 the authors compared the
`efficacy and safety of 12 weeks of treatment with
`the combination product fluticasone propionate
`100 µg and salmeterol 50 µg administered
`twice/day versus montelukast 10 mg once/day as
`add-on therapy (i.e., fluticasone propionate plus
`salmeterol vs fluticasone propionate plus
`montelukast) in adults and adolescents with
`asthma suboptimally controlled with inhalation
`corticosteroid therapy. Treatment with the
`combination product resulted in significantly
`greater improvements in morning and evening
`PEF, FEV1, and shortness of breath and a
`reduction in the need for rescue albuterol and
`exacerbations compared with fluticasone
`propionate plus montelukast.
`
`Inhaled Corticosteroid with a Long-Acting b2-
`Agonist
`
`Efficacy
`
`Several studies compared the efficacy of the
`concurrent administration of a long-acting b2-
`agonist with an inhaled corticosteroid (or both
`classes of drugs in a single product) with that of
`placebo, the individual agents alone, budesonide,
`triamcinolone acetonide, or montelukast.34, 47, 48,
`70–73 These studies demonstrated that the
`combination of salmeterol and fluticasone
`propionate (at low and medium dosages)
`significantly improved pulmonary function and
`asthma symptom control and reduced the need
`for rescue albuterol compared with placebo, the
`individual
`agents
`alone, budesonide,
`triamcinolone acetonide, or montelukast in
`patients with asthma previously treated with or
`without an inhaled corticosteroid.
`
`Placebo
`In one 4-week study,70 the authors reported the
`superior efficacy of concurrent treatment with
`salmeterol 42 µg and fluticasone propionate at
`both the 88- and 220-µg doses administered
`through a metered-dose inhaler (MDI) compared
`with placebo in improving FEV1 and asthma
`symptom control and reducing the need for
`rescue albuterol in 136 adults and adolescents
`previously treated with short-acting b2-agonists
`
`alone. The authors of two 12-week studies47, 48
`reported similar results to those of the 4-week
`study with the combination product (salmeterol
`50 µg with fluticasone propionate either 100 µg
`or 250 µg) administered as an inhaled powder in
`adults and adolescents (705 patients) previously
`treated with either salmeterol48 or an inhaled
`corticosteroid.47, 48 Patients treated with the
`combination product were significantly less likely
`to withdraw from either of these studies due to
`worsening of asthma compared with those
`receiving placebo.
`
`Individual Agents Alone
`
`Several studies compared the efficacy of
`concurrent use of a long-acting b2-agonist and an
`inhaled corticosteroid (or a combination
`product) with the individual agents alone.46–48, 70,
`74 In patients previously treated with low to high
`dosages of an inhaled corticosteroid46–48, 74 or
`long- or short-acting b 2-agonists alone,47, 70
`treatment with salmeterol plus low to medium
`dosages of an inhaled corticosteroid (used either
`concurrently or in a combination product)
`significantly improved FEV1 or PEF and/or
`asthma symptom control compared with inhaled
`corticosteroids46–48, 70 or long-acting b2-agonists
`alone.47, 48
`
`No Previous Treatment with Inhaled Corticosteroids
`
`In a small, double-blind, double-dummy pilot
`study of 136 patients (21–25 patients in each
`treatment arm) with asthma not previously
`treated with inhaled corticosteroids, concurrent
`treatment with salmeterol and fluticasone
`propionate either 88 or 220 µg twice/day for 4
`weeks significantly improved predose FEV1
`compared with salmeterol, fluticasone propionate
`88 µg, or fluticasone propionate 220 µg alone.
`Concurrent treatment significantly increased
`morning and evening PEF, area under the 12-
`hour serial FEV1 curve, percentage of nights with
`no awakenings, and percentage of days with no
`symptoms and reduced symptom scores
`compar