Dual-Controller Asthma Therapy: Rationale and Clinical Benefits

Transcription

1 B/1 Dual-Controller Asthma Therapy: Rationale and Clinical Benefits MODULE B The 1997 National Heart, Lung, and Blood Institute (NHLBI) Expert Panel guidelines on asthma management recommend a 4-step approach to asthma therapy based on the level of asthma severity: mild intermittent asthma, mild persistent asthma, moderate persistent asthma, or severe persistent asthma. For any patient with persistent asthma (steps 2, 3, or 4), inhaled corticosteroids are the cornerstone of care because of their robust efficacy and potent anti-inflammatory effects. This slide set reviews the newest clinical data regarding asthma management at steps 3 and 4, when combination therapy (that includes inhaled corticosteroids) is nearly always warranted. National Asthma Education and Prevention Program. Guidelines for the Diagnosis and Management of Asthma. Bethesda, Md: US Dept of Health and Human Services, National Institutes of Health; NIH Publication no Advanced Studies in Medicine 21

2 B/2 Dual-Controller Therapy Concurrent administration of two medications with complementary mechanisms of action A recommended treatment strategy for patients with persistent asthma in the 1997 National Heart, Lung, and Blood Institute (NHLBI) guidelines One of two broad strategies for patients inadequately controlled on inhaled corticosteroids alone Increase dose of inhaled corticosteroid (ie( ie,, remain on monotherapy) Add second complementary therapy (ie( ie,, initiate dual-controller therapy) National Asthma Education and Prevention Program. Guidelines for the Diagnosis and Management of Asthma. Bethesda, Md: US Dept of Health and Human Services, National Institutes of Health; NIH Publication no The use of dual-controller therapy that is, the concurrent administration of two controller medications with complementary mechanisms of action is one of the treatment strategies recommended in the 1997 National Heart, Lung, and Blood Institute (NHLBI) guidelines for patients with persistent asthma. Dual-controller therapy is one of two broad treatment strategies for patients whose asthma is inadequately controlled with inhaled corticosteroids, which are longterm controller medications that improve asthma symptoms, normalize lung function, and help to mitigate damage to the airways by virtue of their anti-inflammatory mechanism of action. In patients whose asthma is inadequately controlled with inhaled corticosteroids, the NHLBI guidelines suggest either increasing the dose of inhaled corticosteroids (ie, remaining on monotherapy) or adding another long-term controller therapy (ie, initiating dual-controller therapy). National Asthma Education and Prevention Program. Guidelines for the Diagnosis and Management of Asthma. Bethesda, Md: US Dept of Health and Human Services, National Institutes of Health; NIH Publication no Advanced Studies in Medicine 22

3 B/3 Comparing the Therapeutic Options Dual-controller therapy versus increasing inhaled corticosteroid dose Dual-controller therapy versus monotherapy with a leukotriene modifier Comparisons among dual-controller regimens A substantial body of data, which postdates the 1997 NHLBI guidelines, demonstrates that dualcontroller therapy confers better efficacy than monotherapy (ie, than either increasing the dose of inhaled corticosteroids or using a leukotriene modifier alone) for initial maintenance therapy as well as for asthma inadequately controlled on inhaled corticosteroids alone. Moreover, the data suggest that certain combination regimens used in dual-controller therapy are more effective than others. This slide set reviews these data. First, studies comparing the efficacy of dual-controller therapy with that of increasing the dose of the inhaled corticosteroid are considered. Then, studies comparing the efficacy of dual-controller therapy with that of monotherapy with a leukotriene modifier are discussed. Finally, studies comparing different dual-controller regimens (ie, an inhaled corticosteroid plus a long-acting β 2 -agonist versus an inhaled corticosteroid plus a leukotriene modifier) are reviewed. Advanced Studies in Medicine 23

4 B/4 Asthma Has Two Pathophysiologic Components Smooth muscle dysfunction Airway inflammation Bronchoconstriction Bronchial hyperreactivity Hyperplasia/hypertrophy Inflammatory mediator release Inflammatory cell infiltration/activation Mucosal edema Cellular proliferation Epithelial damage Basement membrane thickening Symptoms/Exacerbations Chung KF, Adcock IM. Pathophysiological mechanisms of asthma. Application of cell and molecular biology techniques. Mol Biotechnol. 2001;18: Why should dual-controller therapy be more effective than monotherapy with inhaled corticosteroids? It is now well established that asthma arises from two main pathophysiologic components: (1) dysfunction of the airway smooth muscles, which leads to bronchoconstriction, bronchial hyperreactivity, and smooth muscle hypertrophy and hyperplasia; and (2) inflammation of the airways, which leads to activation and accumulation of inflammatory cells; edema; damage to the airway epithelium; and thickening of the airway basement membrane. 1 Medications used with inhaled corticosteroids in dual-controller regimens include long-acting β 2 -agonists and leukotriene modifiers. Neither of these classes of medication has a mechanism of action that overlaps completely with that of the inhaled corticosteroids with which they are combined in dual-controller regimens. The complementary mechanisms of components of dualcontroller regimens are hypothesized to lead to enhanced control of asthma relative to that achievable with single mechanism-of-action therapies. With some dual-controller regimens as with those involving a long-acting bronchodilator and an inhaled corticosteroid both the bronchoconstrictive and the inflammatory components of asthma are targeted. Chung KF, Adcock IM. Pathophysiological mechanisms of asthma. Application of cell and molecular biology techniques. Mol Biotechnol. 2001;18: Advanced Studies in Medicine 24

5 B/5 Dual-Controller Therapy Compared With Increasing Inhaled Corticosteroid Dose Randomized, double-blind, parallel-group, multicenter trial 437 patients with an FEV 1 of 40% to 80% of predicted Randomized to receive either a combination of salmeterol (42 mcg bid) and fluticasone propionate (88 mcg bid) or high-dose fluticasone propionate alone (220 mcg bid) for 24 weeks Condemi JJ, Goldstein S, Kalberg C, et al. The addition of salmeterol to fluticasone propionate versus increasing the dose of fluticasone propionate in patients with persistent asthma. Ann Allergy Asthma Immunol. 1999;82: Several studies have compared the efficacy of dual-controller regimens including a long-acting β 2 -agonist or a leukotriene modifier plus an inhaled corticosteroid with that of increasing the dose of an inhaled corticosteroid in patients whose asthma is poorly controlled on inhaled corticosteroids alone. Uniformly across studies, the addition of a long-acting β 2 -agonist to inhaled regimens of the corticosteroids beclomethasone dipropionate, 1-3 fluticasone propionate, 4,5 or budesonide 6 yields better control of lung function as measured by forced expiratory volume in 1 second (FEV 1 ) or peak expiratory flow rate (PEF) as well as better control of respiratory symptoms than does increasing the dose of inhaled corticosteroids. For example, one randomized, double-blind, parallel-group, multicenter trial enrolled 437 patients (FEV 1 40% to 80% of predicted) who had used fluticasone propionate 88 mcg bid for at least 2 weeks for control of asthma. These patients were randomized to receive either a combination regimen of the long-acting β 2 -agonist salmeterol (42 mcg bid) and the inhaled corticosteroid fluticasone propionate (88 mcg bid) or high-dose fluticasone propionate alone (220 mcg bid) for 24 weeks. 4 s 1. Woolcock A, Lundback B, Ringdal N, et al. Comparison of addition of salmeterol to inhaled steroids with doubling the dose of inhaled steroids. Am J Respir Crit Care Med. 1996;153: Murray JJ, Church NL, Anderson WH, et al. Concurrent use of salmeterol with inhaled corticosteroids is more effective than inhaled corticosteroid dose increases. Allergy Asthma Proc. 1999;20: Greening AP, Ind PW, Northfield M, et al. Added salmeterol versus higher-dose corticosteroid in asthma patients with symptoms on existing inhaled corticosteroid. Lancet. 1994;344: Condemi JJ, Goldstein S, Kalberg C, et al. The addition of salmeterol to fluticasone propionate versus increasing the dose of fluticasone propionate in patients with persistent asthma. Ann Allergy Asthma Immunol. 1999;82: van Noord JA, Schreurs AJM, Mol SJM, et al. Addition of salmeterol versus doubling the dose of fluticasone propionate in patients with mild to moderate asthma. Thorax. 1999;54: Pauwels RA, Löfdahl C-G, Postma DS, et al. Effect of inhaled formoterol and budesonide on exacerbations of asthma. N Engl J Med. 1997;337: Advanced Studies in Medicine 25

6 Results: Dual-Controller Therapy Compared With Increasing Inhaled Corticosteroid Dose MEAN CHANGE FROM BASELINE OVER THE 24-WEEK TREATMENT PERIOD B/6 Variable AM PEF PM PEF Fluticasone + Salmeterol High-Dose Fluticasone 46.5 L/min* 23.8 L/min 38.2 L/min* 21.2 L/min FEV L/min* 0.33 L/min Total symptoms -0.43* % nights no waking 14.9%* 10.1% Mean daily albuterol puffs* puffs *P<0.05 versus higher-dose fluticasone propionate. Note: Symptoms were scored on a 5-point scale (0 = no symptoms; 4 = symptoms causing severe discomfort). Condemi JJ, Goldstein S, Kalberg C, et al. The addition of salmeterol to fluticasone propionate versus increasing the dose of fluticasone propionate in patients with persistent asthma. Ann Allergy Asthma Immunol. 1999;82: The results show that although lung function and symptoms improved compared with baseline in both treatment groups, the group receiving the salmeterol-fluticasone propionate combination exhibited greater improvement than did the high-dose fluticasone propionate group in morning and evening PEF; FEV 1 ; symptoms including wheezing, shortness of breath, and chest tightness; frequency of night awakenings; and supplemental albuterol use. The superiority of the combination regimen to the high-dose corticosteroid regimen at improving lung function was evident by the end of the first treatment week for PEF and by the end of the second treatment week for FEV 1. Condemi JJ, Goldstein S, Kalberg C, et al. The addition of salmeterol to fluticasone propionate versus increasing the dose of fluticasone propionate in patients with persistent asthma. Ann Allergy Asthma Immunol. 1999;82: Advanced Studies in Medicine 26

7 B/7 Dual-Controller Therapy Compared With Monotherapy With a Leukotriene Modifier Randomized, double-blind, parallel-group, multicenter trial 423 patients with an FEV 1 of 50% to 80% of predicted Randomized to receive either fluticasone/salmeterol combination product (100( mcg/50 mcg twice daily) or oral montelukast (10 mg once daily) for 12 weeks ADVAIR Diskus Clinical Monograph. The GlaxoSmithKline Group of Companies; April Dual-controller therapy has also been shown to confer better control of asthma than monotherapy with leukotriene modifiers. The effects of dual-controller therapy with a combination product containing the inhaled corticosteroid fluticasone propionate and the long-acting β 2 -agonist salmeterol have been compared with those of monotherapy with a leukotriene modifier in two studies that yielded comparable results. For example, in the first study a randomized, double-blind, parallel-group, multicenter trial 423 patients remaining symptomatic on short-acting β 2 -agonist were randomized to treatment with the fluticasone/salmeterol combination product (100 mcg/50 mcg twice daily) or the leukotriene modifier montelukast (10 mg once daily) for 12 weeks. ADVAIR Diskus Clinical Monograph. The GlaxoSmithKline Group of Companies; April Advanced Studies in Medicine 27

8 Results: Dual-Controller Therapy Compared With Monotherapy With a Leukotriene Modifier MEAN CHANGE FROM BASELINE OVER THE 24-WEEK TREATMENT PERIOD Variable Fluticasone + Salmeterol Montelukast AM PEF 89.9 L/min* 34.2 L/min PM PEF 69.9 L/min* 31.1 L/min FEV L/min* 0.27 L/min Daytime symptoms -1.0* -0.6 % nights no waking 49.2%* 31.4% B/8 *P<0.05 versus montelukast. Note: Symptoms were scored on a 5-point scale (0 = no symptoms; 4 = symptoms causing severe discomfort). ADVAIR Diskus Clinical Monograph. The GlaxoSmithKline Group of Companies, April The results show that mean morning predose FEV 1 increased by 23% from baseline in patients treated with fluticasone propionate/salmeterol compared with 11% in patients treated with montelukast (P<0.05). Secondary end points including mean changes in PEF and symptom scores also favored the fluticasone/salmeterol combination over montelukast. Similar results were reported in a second 12-week study comparing the fluticasone/salmeterol combination product (100 mcg/50 mcg twice daily) with montelukast (10 mg once daily) for 12 weeks in 432 patients. The more robust efficacy of this dual-controller regimen may be attributable to the dual mechanism of action of the combination, which combats both the inflammatory and bronchoconstrictive components of asthma. ADVAIR Diskus Clinical Monograph. The GlaxoSmithKline Group of Companies; April Advanced Studies in Medicine 28

9 B/9 Comparisons Among Dual-Controller Regimens Two identical randomized, double-blind, parallel- group studies 948 patients with an FEV 1 of 68% to 69% of predicted Randomized to receive either salmeterol (50( mcg twice daily) or oral montelukast (10 mg once daily) in addition to stable inhaled corticosteroid regimen for 12 weeks Fish JE, Israel E, Murray JJ, et al. Salmeterol powder provides significantly better benefit than montelukast in asthmatic patients receiving concomitant inhaled corticosteroid therapy. Chest. 2001;120: Based on the different mechanisms of action of long-acting β 2 -agonists and leukotriene modifiers, dual-controller regimens composed of inhaled corticosteroid long-acting bronchodilator combinations might be expected to be more effective than dual-controller regimens composed of inhaled corticosteroids and leukotriene modifiers. Whereas the former dual-controller regimen has activity against both major pathophysiologic components of asthma (ie, inflammation and smooth muscle dysfunction), the latter dual-controller regimen is primarily anti-inflammatory. In fact, clinical studies suggest that the combination of an inhaled corticosteroid and a long-acting β 2 -agonist is more effective than the combination of an inhaled corticosteroid with a leukotriene modifier. For example, Fish et al reported the results of two identical, randomized, double-blind, doubledummy, parallel-group studies of 948 patients with persistent asthma whose symptoms were inadequately controlled with inhaled corticosteroids alone. Either the long-acting β 2 -agonist salmeterol (50 mcg twice daily by inhalation) or the leukotriene modifier montelukast (10 mg once daily by mouth) was added to stable doses of patients inhaled corticosteroids (ie, beclomethasone dipropionate, budesonide, fluticasone propionate, flunisolide, or triamcinolone acetonide) for a 12-week treatment period. Fish JE, Israel E, Murray JJ, et al. Salmeterol powder provides significantly better benefit than montelukast in asthmatic patients receiving concomitant inhaled corticosteroid therapy. Chest. 2001;120: Advanced Studies in Medicine 29

10 B/10 Results: Comparisons Among Dual-Controller Regimens MEAN CHANGE FROM BASELINE OVER THE 24-WEEK TREATMENT PERIOD Variable Corticosteroid + Salmeterol Corticosteroid + Montelukast AM PEF 35.0 L/min* 21.7 L/min PM PEF 27.8 L/min* 19.0 L/min % symptom-free days 24%* 16% Daytime symptoms -0.55* Nights waking/week -1.42* *P<0.05 versus inhaled corticosteroid + montelukast. Note: Symptoms were scored on a 5-point scale (0 = no symptoms; 4 = symptoms causing severe discomfort). Fish JE, Israel E, Murray JJ, et al. Salmeterol powder provides significantly better benefit than montelukast in asthmatic patients receiving concomitant inhaled corticosteroid therapy. Chest 2001;120: The results demonstrate that the addition of salmeterol compared with the addition of montelukast to the inhaled corticosteroid regimen was associated with significantly greater improvement from baseline in lung function as measured by morning PEF (35.0 vs 21.7 L/min, P<.001) and evening PEF (27.8 vs 19.0 L/min, P = 0.002). Furthermore, dual-controller therapy with salmeterol plus an inhaled corticosteroid compared with dual-controller therapy with montelukast plus an inhaled corticosteroid: Improved total symptom scores for shortness of breath and chest tightness; Increased the number of symptom-free days and days with no requirement for rescue medications; Decreased supplemental albuterol use; and Reduced the number of nighttime awakenings per week. 1 A similar pattern of results was reported in a randomized, double-blind clinical trial comparing the efficacy and tolerability of fluticasone propionate (100 mcg) plus salmeterol (50 mcg) twice daily with that of fluticasone propionate (100 mcg) twice daily plus oral montelukast (10 mg) once daily in 447 patients with asthma who remained symptomatic on the inhaled corticosteroid alone. 2 s 1. Fish JE, Israel E, Murray JJ, et al. Salmeterol powder provides significantly better benefit than montelukast in asthmatic patients receiving concomitant inhaled corticosteroid therapy. Chest. 2001;120: Nelson HS, Busse WW, Kerwin E, et al. Fluticasone propionate/salmeterol combination provides more effective asthma control than low-dose inhaled corticosteroid plus montelukast. J Allergy Clin Immunol. 2000;106: Advanced Studies in Medicine 30

11 B/11 Conclusions Data support NHLBI recommendations for dual-controller therapy with an inhaled corticosteroid plus a long-acting β 2 -agonist in patients with moderate persistent or severe persistent asthma Combination of an inhaled corticosteroid plus a long- acting β 2 -agonist is more effective than: Increasing the dose of an inhaled corticosteroid; Monotherapy with a leukotriene modifier; or Dual-controller therapy involving an inhaled corticosteroid and a leukotriene modifier. Considered together, these data support NHLBI recommendations for dual-controller therapy with an inhaled corticosteroid and a long-acting β 2 -agonist in patients with moderate persistent or severe persistent asthma. The results show that the combination of an inhaled corticosteroid and a long-acting β 2 -agonist is more effective at improving lung function and asthma symptoms than is (1) increasing the dose of an inhaled corticosteroid; (2) monotherapy with a leukotriene modifier; or (3) dual-controller therapy involving an inhaled corticosteroid and a leukotriene modifier. Advanced Studies in Medicine 31