# Presentation: 830671

## Clinical Implications: The Need for LABAs

**James F. Donohue, MD**
**Professor of Medicine****Chief of Pulmonary Division**
**University of North Carolina, Chapel Hill, NC**

**4**

## Life Before LABAs

**Alternatives**
**SABAs, theophylline, epinephrine,****oral β-agonists**
**Treatment effects/disadvantages**
**Rollercoaster effect**
**Lack of nocturnal coverage**
**SABA compliance**
**Concern in school-aged children who need to be dosed frequently**

## Life Before LABAsSABAs

**SABA overusage**
**Tremor**
**Hypokalemia**
**Tachycardia**
**Hyperglycemia**
**Saskatchewan data**

## Asthma Death Rates by Inhaledβ-Agonist Use

**1**

**2**

**3**

**4**

**5**

**6**

**7**

**8**

**0**

**50**

**0**

**100**

**150**

**200**

**250**

**Death rate**** per 10,000 per year**

**Canister units (20,000 μg of****β-agonist per month)**

**Suissa S, et al. *****Am J Respir Crit Care Med***** 1994;149:604-610. **

**23**

## Life Before LABAs—Side-effect Profile of Theophylline and Oral Corticosteroids

**Increased use of theophylline**
**Narrow therapeutic window**
**Drug-drug interactions**
**GI and cardiovascular side effects**
**Insomnia/convulsions**
**Oral corticosteroids **
**HPA and growth suppression**
**Osteoporosis/fractures**
**Diabetes**
**Hypertension**
**Glaucoma **
**Capillary fragility/skin thinning**
**Psychological effects**
**Immune suppression**

## Worldwide Variation in Prevalenceof Asthma SymptomsInternational Study of Asthma and Allergies in Childhood (ISAAC)

***Lancet *****1998;351:1225-1232.**

**MBM 6-6-05 GINASlideset2004.ppt s18**

**3**

**0**

**5**

**10**

**15**

**20**

**25**

**30**

**35**

**40**

**Prevalence rate of****asthma symptoms, %**

## Age-Adjusted Asthma-Related Death Ratesin the United States by Race

**Age-Adjusted Asthma-Related Death Rates****in the United States by Race**

**† ****Nonwhite from 1960 to 1967.**
**FDC = Fixed dose combination.****Centers for Disease Control and Prevention. Compressed Mortality File: Underlying Causes of Death, 1979 - 2001.**** Available at http://wonder.cdc.gov/mortSQL.html.****National Center for Health Statistics, Division of Vital Statistics. Unpublished mortality tabulations for 113 selected causes by 10-year age groups, race, and sex for 2001 and 2002. Personal communication. 2004**

**NHLBI Chart book on cardio lung-blood Chart 4-28**

**17**

**LABAs****introduced**

**ICS introduced**

**SABAs**
**introduced**

**Fluticasone**

**LABA****FDC**

**NHLBI guidelines**

## LABAs Confer Benefits in the Treatment of Asthma

**More consistent bronchodilation**
**Reduction in “roller-coaster” effect **
**Greater control of nocturnal symptoms**
**Improved morning lung function (PEF)**
**Reduced diurnal lung function variability **
**Prolonged  protection against exercise-induced bronchospasm**

## Foradil® Efficacy in Patients With Asthma

**Efficacy established in **
**3 pivotal trials in asthma (n = 1613)**
**Significant improvement in**
**Superior FEV****1**** vs placebo over 12 hr **
**Duration of action sustained over 12 wk**
**Reduced need for nighttime rescue medication****†**
**Onset of action similar to albuterol**

**4**

**† ****Bensch G, et al. *****Ann Allergy Asthma Immunol*****. 2001;86:19-27.**

## Sustained Improvement in FEV1 at 12 Wk Studies 040 and 041

**0**

**5**

**10**

**15**

**20**

**25**

**30**

**35**

**40**

**0**

**15**

**1**

**3**

**5**

**7**

**9**

**11**

**Mean change from baseline, %**

**Study 040**

**Hr**

**Min**

**0**

**5**

**10**

**15**

**20**

**25**

**30**

**35**

**40**

**0**

**15**

**1**

**3**

**5**

**7**

**9**

**11**

**Formoterol 12 μg**

**Albuterol 180 μg**

**Placebo**

**Hr**

**Min**

**Ciba Protocol 040 CGP 25827A Exhibit 8.1-5; Protocol 041 25827A Exhibit 8.1-5**

**Study 041**

**Data on file. Novartis Pharmaceuticals.**

**12**

**12**

## Foradil® Reduces Rescue Medication Use Studies 040 and 041

**0.0**

**0.5**

**1.0**

**1.5**

**2.0**

**2.5**

**Run-in**

**4**

**8**

**12**

**Week**

**Median puffs, n**

**Study 040**

**Study 041**

**0.0**

**0.5**

**1.0**

**1.5**

**2.0**

**2.5**

**Run-in**

**4**

**8**

**12**

**Week**

**Formoterol 12 μg**

**Albuterol 180 μg**

**Placebo**

**Ciba Protocol 040 CGP 25827A Exhibit 8.1-19; Ciba Protocol 041 CGP25827A Exhibit 8.1-20**

*** *****P***** < .001 vs placebo**
**Data on file. Novartis Pharmaceuticals.**

*****

*****

*****

*****

*****

*****

## Foradil® Reduces Nocturnal Asthma Symptom Score Studies 040 and 041

**0.0**

**0.2**

**0.4**

**0.6**

**0.8**

**1.0**

**Run-in**

**4**

**8**

**12**

**Week**

**Median symptom score**

**Study 040**

**Study 041**

**0.0**

**0.2**

**0.4**

**0.6**

**0.8**

**1.0**

**Run-in**

**4**

**8**

**12**

**Week**

**Formoterol 12 μg**

**Albuterol 180 μg**

**Placebo**

**Ciba Protocol 040 CGP 25827A Exhibit 8.1-11; Ciba Protocol 041 CGP25827A Exhibit 8.1-11**

*** *****P***** < .001 vs placebo; ** *****P***** = .004 vs placebo; *** *****P***** = .002 vs placebo.**
**Data on file. Novartis Pharmaceuticals.**

*****

*****

*****

*****

******

*******

## Improvement in FEV1

**90**

**75**

**80**

**85**

**–****1**

**3**

**9**

**0**

**2**

**12**

**Month**

**Higher-dose BUD plus formoterol**

**Lower-dose BUD plus formoterol**

**Higher-dose BUD **

**Lower-dose BUD **

**FEV****1****, % predicted**

**1**

**6**

**FEV****1**** = Forced expiratory volume in 1 second.**
**Pauwels RA, et al. *****New Engl J Med.***** 1997;337:1405-1411.**

**Pauwels et al NEJM 337_1405-1411,1997.pdf F 1**

**16 DV**

**Run-in**

## Interaction Between LABAs and ICS on Asthma Control

**Pauwels et al NEJM 337_1405-1411,1997.pdf T 2**

**61.4**

**70.3**

**71.8**

**80.8**

**0**

**20**

**40**

**60**

**80**

**100**

**Patients without severe exacerbation, %**

**Lower-dose BUD plus placebo**

**Lower-dose BUD plus formoterol**

**Higher-dose BUD plus placebo**

**Higher-dose BUD plus formoterol**

**16 DV**

**BUD = Budesonide.**
**Pauwels RA, et al. *****New Engl J Med*****. 1997;337:1405-1411.**

## NHLBI Guidelines—Stepwise Approach to Asthma Therapy†

**NHLBI Guidelines—Stepwise Approach to Asthma Therapy****†**

**Reliever: Rapid-acting inhaled β****2****-agonist PRN**

**Controller:**
**Low-dose****inhaled corticosteroid or **
**Cromolyn or nedocromil or**
**Theophylline-SR**
**Leukotriene****modifier**

**Controller:**
**Medium dose inhaled corticosteroid *****or***
**Low- to medium-dose inhaled corticosteroid *****plus***** long-acting inhaled****β****2****-****agonist**
**(if needed) medium-to-high dose inhaled corticosteroid and long-acting bronchodilator**

**Controller:**
**High-dose inhaled corticosteroid *****and***
**Long-acting inhaled****β****2****-****agonist**** **
**Theophylline-SR *****or***
**Long-acting β2-agonist tablets **
***	******plus *****long-term oral corticosteroid**

**STEP 1:**
**Mild intermittent**

**STEP 4:**
**Severe persistent**

**STEP 3:**
**Moderate persistent**

**STEP 2:**
**Mild persistent**

**Controller:**
**None**

**SR = Sustained release.**
**NIH Publication. 1997. No 97-4031.****† Patients > 5 yr of age.**

## LABAs Are Established as Part of the Current Standard of Asthma Treatment

**Internationally accepted guidelines**
**Well established that LABAs have a place in the treatment regimen for asthma in conjunction with ICS**
**No alternative inhaled controller bronchodilator available for asthma**

## Conclusions

**LABAs have provided documented improvements in symptoms, airway function, and QoL**
**Since introduction of LABAs and controllers, asthma hospitalizations and mortality have decreased**
**LABAs in conjunction with ICS represent a medication category critical for optimal care of patients with moderate to severe asthma **