The Safe Use of Long-Acting Beta-Adrenoceptor Agonists

1
The Safe Use of Long-Acting Beta-Adrenoceptor
Agonists LABAs The Importance of
differentiating Asthma from COPD

• Anthony D. DUrzo MD, MSc, CCFP, FCFP
• Associate Professor,
• Department of Family and Community Medicine
• University of Toronto
• Chair, Primary Care Respiratory Alliance of
  Canada (PCRC)
• Director, Primary Care Lung Clinic, Toronto
• www.lungclinic.ca

2
The Safe Use of Long-Acting Beta-Adrenoceptor
Agonists LABAs The Importance of
differentiating asthma from COPD

• Reuven Jhirad MD, CCFP, FCFP
• Lecturer,
• Department of Family and Community Medicine
• University of Toronto
• Member , Primary Care Respiratory Alliance of
  Canada (PCRC)

3
Disclosure

• Anthony D. DUrzo Have received speaker fees
  and research grants from several pharmaceutical
  organizations to participate in educational
  events and research activities involving the role
  of LABAs in asthma and COPD management.

4
Disclosure

• Revven Jhirad none declared

5
The Safe Use of Long-Acting Beta-Adrenoceptor
Agonists LABAs The Importance of
differentiating Asthma from COPD

• Acknowledegments
• Dr Itamar Tamari (DFCM, U of T)
• Dr Pieter Jugovic (DFCM, U of T)
• Dr Jacques Bouchard (University of Montreal)
• Members Primary Care Respiratory Alliance of
  Canada (PCRC)

6
The Safe Use of Long-Acting Beta-Adrenoceptor
Agonists LABAs The Importance of
differentiating Asthma from COPD

• Objectives
• Historical perspective on beta-agonist safety
• review safety concerns around LABA use in asthma
  management
• discuss the role of LABAs in the management of
  chronic obstructive pulmonary disease (COPD)
• discuss the importance of differentiating asthma
  from COPD and the risk of disease
  misclassification

7
The Safe Use of Long-Acting Beta-Adrenoceptor
Agonists LABAs The Importance of
differentiating Asthma from COPD

• Historical Perspective
• Spitzer W.O et al. N Engl J Med 1992 326 501-6
• use of beta-agonists (especially fenoterol)
  administered by MDI associated with increased
  risk of death from asthma (O.R. 2.6 per canister
  /month)
• Castle et al. BMJ 1993 306 (6884) 1034-7
• Numerical increase (3 fold) in asthma deaths with
  salmeterol use compared to salbutamol.
• UK General Practitioners (25,180 patients)
• metered dose inhaler

8
The Safe Use of Long-Acting Beta-Adrenoceptor
Agonists LABAs The Importance of
differentiating Asthma from COPD

• Historical Perspective
• DUrzo AD et al. Chest 2001 119 (3) 714-9
• Effectiveness and safety of salmeterol in
  Nonspecialist practice settings
• Salmeterol treatment is effective in asthmatic
  subjects typically cared for in the primary care
  setting and does not increase the frequency of
  severe exacerbations.

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The Safe Use of Long-Acting Beta-Adrenoceptor
Agonists LABAs The Importance of
differentiating Asthma from COPD

• Pauwels RA et al. N Engl J Med. 1997 337 (20)
  1405-11
• Formoterol And Corticosteroids Establishing
  Therapy (FACET)
• addition of formoterol to budesonide therapy
  improves symptoms (exacerbations) and lung
  function compared to budesonide alone.

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The Safe Use of Long-Acting Beta-Adrenoceptor
Agonists LABAs The Importance of
differentiating Asthma from COPD

• OByrne PM et al. Am J Respir Crit Care Med 2001
  164(8) 1392-1397
• Low dose Inhaled budesonide and formoterol in
  mild persistent asthma
• In corticosteroid free patients, low dose
  inhaled budesonide alone reduced severe
  exacerbations and improved asthma control
• In patients already receiving inhaled
  corticosteroids, adding formoterol was more
  effective than doubling the corticosteroid dose

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The Safe Use of Long-Acting Beta-Adrenoceptor
Agonists LABAs The Importance of
differentiating Asthma from COPD

• Bateman ED et al. Am J Respir Crit Care Med 2004
  170 (8) 836-44
• Can Guideline defined asthma control be
  achieved? The Gaining Optimal Asthma Control
  Study.
• asthma control achieved more rapidly and at a
  lower corticosteroid dose with salmeterol /
  fluticasone vs fluticasone
• Exacerbation rates and health status were
  significantly better with salmeterol /
  fluticasone.

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The Safe Use of Long-Acting Beta-Adrenoceptor
Agonists LABAs The Importance of
differentiating Asthma from COPD

• A Controversy Emerges
• Nelson HS et al. Chest 2006 129 (1) 15-26
• The Salmeterol Multicenter Asthma Research
  Trial a comparison of usual pharmacotherapy for
  asthma or usual pharmacotherapy plus salmeterol
  (SMART)
• drug manufacturer asked by the FDA to conduct a
  post marketing surveillance study which began in
  1996.

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Nelson HS et al. Chest 2006 129 (1) 15-26
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The Safe Use of Long-Acting Beta-Adrenoceptor
Agonists LABAs The Importance of
differentiating Asthma from COPD

• A Controversy Emerges
• Salpter ER et al. Ann Intern Med 2006 144 (12)
  904 -12
• Meta-analysis effect of long-acting
  B2-agonists on severe asthma exacerbations and
  asthma related deaths
• conclusions based primarily on the results of
  SMART trial, Nelson HS et al. Chest 2006 129
  (1) 15-26

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The Safe Use of Long-Acting Beta-Adrenoceptor
Agonists LABAs The Importance of
differentiating Asthma from COPD

• The Food and Drug Administration addresses the
  Controversy around LABA safety in Asthma
  Management 2008
• Expert panel warns against continued use of
  salmeterol and formoterol as monotherapy for
  adults and children with asthma
• www.fda.gov/ohrms/dockets/ac/08/transcripts/2
  008.43982-day2.pdf.
• Accessed 2009 Dec 16

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The Safe Use of Long-Acting Beta-Adrenoceptor
Agonists LABAs The Importance of
differentiating Asthma from COPD

• Jaeschke R. et al. Am J Respir Crit Care Med
  2008 1781009-1016
• The Safety of Long-Acting B-agonists (LABA)
  among patients with asthma using Inhaled
  Corticosteroids Systemic Review and Meta-
  analysis.
• in the patients using inhaled corticosteroids,
  LABA use did not increase the risk of asthma
  related hospitalizations.

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The Safe Use of Long-Acting Beta-Adrenoceptor
Agonists LABAs The Importance of
differentiating Asthma from COPD

• Current Perspective
• Safety of long-acting B2-agonists (LABA) in
  the management of asthma A Primary Care
  Respiratory Alliance of Canada (PCRC) Perspective
• Can Fam Physician 2010 56 119-20
• LABAs should be added if symptoms are not
  adequately controlled on low-to-moderate dose of
  inhaled corticosteroids.

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The Safe Use of Long-Acting Beta-Adrenoceptor
Agonists LABAs The Importance of
differentiating Asthma from COPD

• FDA Drug Safety Communication New safety
  requirements for long-acting inhaled asthma
  medications called Long-acting Beta-Agonists
  (LABAs). Safety Announcement (02-18-2010)
• The use of LABAs is contraindicated without the
  use of an asthma controller medication such as an
  inhaled corticosteroid. Single-ingredient LABAs
  should only be used in combination with an asthma
  controller medication they should not be used
  alone
• LABAs should only be used long-term in patients
  whose asthma cannot be adequately controlled on
  asthma controller medications
• LABAs should be used for the shortest duration of
  time required to achieve control of asthma
  symptoms and discontinued, if possible, once
  asthma control is achieved. Patients should then
  be maintained on an asthma controller medication
• Pediatric and adolescent patients who require the
  addition of a LABA to an inhaled corticosteroid
  should use a combination product containing both
  an inhaled corticosteroid and a LABA, to ensure
  compliance with both medications

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The Safe Use of Long-Acting Beta-Adrenoceptor
Agonists LABAs The Importance of
differentiating Asthma from COPD

• Current Perspective
• Canadian Thoracic Society Asthma Committee
  commentary on long-acting beta-2-agonist use for
  asthma in Canada
• Lougheed MD, et al. Can Respir J 2010 17(2)
  57-8
• Concur with FDA but caution that the FDA
  recommendation that LABA be used for the
  shortest duration possible to achieve control of
  asthma symptoms and then discontinued is not
  evidence based.

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Differentiating Asthma from COPD

• Why is this important?

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Differentiating Asthma from COPD

• First Line Therapy
• Asthma - Inhaled glucocorticosteroids
• COPD - Inhaled bronchodilator therapy long
  acting for maintenance ? hyperinflation
  ? inspiratory capacity
• IMPORTANT
• Long-acting-ß2-agonist monotherapy
  contraindicated in ASTHMA

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Differentiating Asthma from COPD
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Role of Spirometry in COPD DiagnosisCOPD
Diagnosis Confirmed by Spirometry Airflow
Obstruction
Consistent reduction in the ratio of FEV1/FVC
lt 0.70 or LLN LLN lower limit of normal
FEV1 Forced expiratory volume in one second
FVC Forced vital capacity
ODonnell DE et al. CTS Recommendations for
Management of COPD. 2008 Update Highlights for
Primary Care. Can Resp J 2008 15(SupplA) 1A-8A
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Role of Spirometry in Asthma Diagnosis

• Increased FEV1 by 12 or 200 cc after B2-agonist
  challenge
• FEV1/FVC not formerly included in diagnostic
  decision making
• CMAJ 1999 161 51-61.

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FEV1 Maximal volume of air exhaled after a
maximal inhalation in the first second of a
forced exhalationFVC Maximal volume of air
exhaled after inhalation during a forced
exhalation FVC lt 80 predicted full pulmonary
function tests (PFTs) to rule out hyperinflation
vs. combined obstructive and restrictive
defect FVC gt 80 predictedFEV1 and FVC lt
80 predictedThe change is calculated as
Postbronchodilator FEV1 Prebronchodilator FEV1
divided by the Prebronchodilator FEV1. FEV1 may
not improve after ß2-agonist challenge.Lack
of change in FEV1 is non-diagnostic referral for
Methacholine challenge recommended.
Can Fam Physician, in press
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Can Fam Physician, in press
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Summary/Conclusion

• LABAs should not be used as monotherapy in asthma
  
• In asthma patients who remain symptomatic on
  regular ICS medication, addition of LABA therapy
  may improve asthma control
• LABAs can be used as monotherapy in patients with
  COPD
• Using historical and spirometric data may
  facilitate differention of asthma from COPD and
  minimize inappropriate therapeutic intervention