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The Long-Acting Beta Agonist: Asthma Therapeutic Friend or Foe

The Long-Acting Beta Agonist: Asthma Therapeutic Friend or Foe. Jason E. Knuffman, M.D. Allergy & Immunology Fellow Department of Medicine July 19, 2006. No Disclosures ICS – Inhaled corticosteroid LABA – Long-acting beta agonist. Outline. Introduction

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The Long-Acting Beta Agonist: Asthma Therapeutic Friend or Foe

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  1. The Long-Acting Beta Agonist:Asthma Therapeutic Friend or Foe Jason E. Knuffman, M.D. Allergy & Immunology Fellow Department of Medicine July 19, 2006

  2. No Disclosures ICS – Inhaled corticosteroid LABA – Long-acting beta agonist

  3. Outline • Introduction • Asthma Clinical Research Network (ACRN) • Salmeterol Multicenter Asthma Research Trial (SMART) • Black Box Warning • Controversy • Conclusions

  4. Long-Acting Beta Agonists • Salmeterol xinafoate (Serevent Diskus and aerosol inhaler) • 50 mcg DPI • 1 puff BID • Delayed onset of action • Advair Diskus (salmeterol combined with fluticasone)

  5. Long-Acting Beta Agonists • Formoterol fumarate (Foradil Aerolizer) • 12 mcg DPI • 1 puff BID • Immediate and delayed onset of action • Symbicort Turbuhaler (formoterol combined with budesonide) • Not available in U.S.

  6. http://www.acrn.org/index.html

  7. After adding LABA to the ICS, my patient’s asthma is under good control. How far can I cut back on their ICS dose?

  8. SLIC (ACRN) • SaLmeterol with or without Inhaled Corticosteroids Trial • Hypothesis: “In patients with persistent asthma who are suboptimally controlled with a regularly-scheduled ICS, but subsequently controlled following the addition of a scheduled LABA, canthe dosage of ICS be reduced or eliminated without increasing the risk of treatment failure?” JAMA.2001;285:2594-2603

  9. SLIC JAMA.2001;285:2594-2603

  10. SLIC • SaLmeterol with or without Inhaled Corticosteroids Trial • Conclusion: “In patients with persistent asthma suboptimally controlled by triamcinolone therapy alone but whose asthma symptoms improve after addition of salmeterol, a substantial reduction (50%) in triamcinolone dose can occur without a significant loss of asthma control. However, total elimination of triamcinolone therapy results in a significant deterioration in asthma control and, therefore, cannot be recommended.” JAMA.2001;285:2594-2603

  11. What about patients well-controlled on ICS, why not switch them to LABA and avoid potential ICS side effects?

  12. Salmeterol Off CorticoSteroids Trial Hypothesis: “In patients with moderate persistent asthma whose symptoms are well-controlled with ICS, does continued treatment with ICS differ in efficacy from a change of therapy with LABA?” SOCS (ACRN) JAMA.2001;285:2583-2593

  13. SOCS JAMA.2001;285:2583-2593

  14. SOCS • Salmeterol Off CorticoSteroids Trial • Conclusion: “In patients with persistent asthma that is well controlled by low-dose triamcinolone monotherapy cannot be switched to salmeterol monotherapy without risk of clinically significant loss of asthma control.” JAMA.2001;285:2583-2593

  15. What about combination (ICS + LABA) therapy and exacerbations?

  16. FACET • Formoterol and Corticosteroids Establishing Therapy Trial • First trial to suggest that adding LABA to ICS could reduce exacerbations • Best way to decrease major exacerbations was to increase ICS four-fold, but… • Adding formoterol to either low- or high-dose ICS (budesonide) further reduced both minor and major exacerbations • These findings supported by…

  17. Optimal Treatment for Mild Asthma (OPTIMA) Trial

  18. Does regular use of LABA make one tolerant to albuterol?

  19. ER Study • Patients seen for acute asthma exacerbations • 57 patients taking salmeterol along with other therapies for asthma • 57 patients not taking salmeterol (controls) • With nebulized albuterol, mean PEF increased from 45% of predicted to 62% in controls, while increasing from 40% to 60% in salmeterol group (p=NS) • No differences seen between length of ER stay, admission to hospital or number of return visits • This and other studies have been reassuring in this matter

  20. Can LABAs be harmful?

  21. SMARTSalmeterol Multicenter Asthma Research Trial A Comparison of Usual Pharmacotherapy for Asthma or Usual Pharmacotherapy plus Salmeterol Nelson HS et al. The salmeterol multicenter asthma research trial: a comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol. Chest. 2006;129:15-26.

  22. SMART Study Design • 28-week, multicenter, randomized, double-blind, placebo-controlled, observational surveillance trial initiated in June 1996 • Target enrollment: ~60,000 patients • Included patients >12 years with asthma currently using a prescription asthma medication • No history of previous salmeterol or formoterol use Nelson HS et al. Chest. 2006;129:15-26.

  23. SMART Study Endpoints • Primary Endpoint • Combined respiratory-related deaths or life-threatening experiences (intubation and ventilation) • Key Secondary Endpoints • Respiratory-related deaths • Combined asthma-related deaths or life-threatening experiences • Asthma-related deaths Nelson HS et al. Chest. 2006;129:15-26.

  24. SMART Study Design (cont.) Salmeterol MDI 42 mcg BID + Usual Care (n=13,176) • No inhaled long-acting beta2-agonist • ≥12 years of age 28-week treatment period Phone contact every 4 weeks R Placebo MDI BID + Usual Care (n=13,179) Clinic Visit 28-week supply of study medication provided Nelson HS et al. Chest. 2006;129:15-26. Adapted with permission.

  25. Baseline Characteristics Salmeterol Placebo (n=13,176) (n=13,179) Age, mean 39.2 39.1 Sex, n (%) Female 8334 (64) 8337 (64) Male 4703 (36) 4686 (36) Ethnic origin, n (%) Caucasian 9281 (71) 9361 (72) African American 2366 (18) 2319 (18) Hispanic 996 (8) 999 (8) Asian 173 (1) 149 (1) Other 230 (2) 224 (2) Peak expiratory flow (% predicted) 84.0 83.8 Nelson HS et al. Chest. 2006;129:15-26. Adapted with permission.

  26. Caucasian African American (n=18,642) (n=4685) Baseline Asthma Characteristics in Caucasians and African Americans 85% 78% Peak expiratory flow (% predicted) Nocturnal symptoms present 67% 59%  1 ER visit last 12 months 22% 41%  1 ER visit lifetime 59% 72%  1 hospitalization last 12 months 6% 15%  1 hospitalization lifetime 30% 44%  1 intubation for asthma lifetime 4% 8% Baseline ICS use 49% 38% Nelson HS et al. Chest. 2006;129:15-26. Adapted with permission.

  27. Asthma Medications at Baseline Salmeterol PlaceboConcurrent Medications, n (%) n=13,176 n=13,179 Patients using asthma medicationsat Baseline 12,715 (97) 12,660 (96) Patients with no asthma medicationsat Baseline 461 (3) 519 (4) Inhaled or oral beta2-agonists(excluding inhaled LABAs) 12,059 (92) 12,043 (91) Inhaled corticosteroids 6127 (47) 6138 (47) Methylxanthines 1766 (13) 1767 (13) Leukotriene modifiers 1437 (11) 1402 (11) Nelson HS et al. Chest. 2006;129:15-26. Adapted with permission.

  28. SMART Interim Analysis, 2002 • SMART did not reach predetermined stopping criteria at the interim analysis • Data Safety Monitoring Board recommended • Timely completion (within 2 years) If this was not possible: • Discontinuation of study and rapid dissemination of the interim results • SMART was discontinued due to difficulties in enrollment and findings in African American patients Nelson HS et al. Chest. 2006;129:15-26.Data on file, GlaxoSmithKline.

  29. 1.40 (0.91, 2.14) 50 36 1.05 (0.62, 1.76) 29 28 4.10 (1.54, 10.90) 20 5 2.16 (1.06, 4.41) 24 11 2.29 (0.94, 5.56) 16 7 3.88 (0.83, 18.26) 8 2 1.71 (1.01, 2.89) 37 22 1.08 (0.55, 2.14) 17 16 4.92 (1.68,14.45) 19 4 4.37 (1.25, 15.34) 13 3 5.82 (0.70, 48.37) 6 1 7.26 (0.89, 58.94) 7 1 SMART ResultsAll Patients and Ethnic Subgroups 1° Endpoint RR (95% CI) SAL n PLA n Combined Respiratory-related Deaths or Life-threatening Experiences 2° Endpoints Respiratory-related Deaths Combined Asthma-related Deaths or Life-threatening Experiences Asthma-related Deaths Total N=13,176 N=13,179 Caucasian N=9281 N=9361 African American N=2366 N=2319 .031 .062 .125 .25 .5 1 2 4 8 16 32 64 128 Nelson HS et al. Chest. 2006;129:15-26.

  30. SMART: Summary of Results • Total Population • For the primary endpoint, 50 events occurred in patients receiving salmeterol vs 36 events in those receiving placebo (RR=1.40, 95% CI [0.91, 2.14]) • A significant increase in respiratory-related deaths was observed in patients receiving salmeterol vs those receiving placebo (RR=2.16, 95% CI [1.06, 4.41]) • The number of combined asthma-related deaths or life-threatening experiences was 37 in patients receiving salmeterol vs 22 in those receiving placebo (RR=1.71, 95% CI [1.01, 2.89]) • A significant increase in asthma-related deaths was observed in patients receiving salmeterol (13 of 13,176 pts) vs those receiving placebo (3 of 13,179 pts) (RR=4.37, 95% CI [1.24, 15.34])

  31. SMART: Summary of Results • African Americans • For the primary endpoint, 20 events occurred in patients treated with salmeterol vs 5 in those treated with placebo (RR=4.10, 95% CI [1.54, 10.90]) • A higher number of respiratory-related deaths (8 vs 2, RR=3.88, 95% CI [0.83, 18.26]) • A higher number of combined asthma-related deaths or life-threatening experiences (19 vs 4, RR=4.92, 95% CI [1.68, 14.45]) • A higher number of asthma-related deaths (7 vs 1, RR=7.26, 95% CI [0.89, 58.94])

  32. SMART: Summary of Results • Caucasians • For the primary endpoint, 29 events occurred in patients treated with salmeterol vs 28 in those treated with placebo (RR=1.05, 95% CI [0.62, 1.76]) • A higher number of respiratory-related deaths (16 vs 7, RR=2.29, 95% CI [0.94, 5.56]) • The number of combined asthma-related deaths or life-threatening experiences was 17 vs 16 (RR=1.08, 95% CI [0.55, 2.14]) • A higher number of asthma-related deaths (6 vs 1, RR=5.82, 95% CI [0.70, 48.37])

  33. SMART: Key Findings • Treatment with salmeterol compared with placebo resulted in statistically significant higher incidence of asthma-related deaths, combined asthma-related deaths or asthma-related life-threatening experiences, and respiratory-related deaths alone • The data from SMART are not adequate to determine, nor was the study designed to determine, whether concurrent use of inhaled corticosteroids, such as fluticasone propionate, modifies this risk of asthma-related death • Given the similar mechanism of action of beta2-agonists, it is possible that the findings of SMART may represent a class effect

  34. http://www.bagoliefriedman.com/news_item.asp?NewsID=382 Hi Dr. Salpeter: This web page, presumably run by an attorney, quoted you as having stated the following under the heading, "News You Can Use": "We estimate that approximately 4,000 out of the 5,000 asthma deaths that occur in the U.S. each year are actually caused by these long-acting beta-agonists, and we urge that these agents be taken off the market," [Shelley Salpeter] added. In the discussion portion of the meta-analysis, you stated, "This indicates that salmeterol may be responsible for approximately 4000 of the 5000 asthma-related deaths that occur in the United States each year (ref.)." I am giving a talk to a large number of area primary care providers next week and your explanation about this wording choice is requested. Thank you! Jason E. Knuffman, MD (608) 516-5645 Madison, WI

  35. LARGE (ACRN) • Long-Acting beta Agonist Response by GEnotype study • 60 week randomized, double-blind, crossover trial to compare the effects of LABA in asthmatics receiving ICS who express two distinct polymorphisms of the beta2-adrenergic receptor • Position 16 Arg/Arg vs. Gly/Gly • Hypothesis: Subjects with the B16 Arg/Arg genotype will experience inferior asthma control (by a.m. PEF rate) than those with the B16 Gly/Gly genotype. • Enrollment of around 80 subjects is now closed with the last subjects finishing in September, 2007.

  36. Conclusions • First-line treatment is the inhaled corticosteroid • LABAs, if selected, should be prescribed only in conjunction with ICS • There may be specific population subsets at elevated risk for poor asthma outcomes while taking LABAs • Pharmacogenomic profiles need to be defined • Documented, informed consent obtained? • Diligent follow-up care is mandatory

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