Update on Treatment of Asthma

1
Update on Treatment of Asthma

• Richard Clarens, PharmD
• UND School of Medicine Health Sciences Dept
  of Family Community Medicine
• Grand Forks Family Medicine Residency Altru
  Health System
• NDSU College of Pharmacy, Nursing, and Allied
  Sciences

2
National Asthma Educationand Prevention Program
(NAEPP) Expert Panel Report 3 Guidelines for the
Diagnosis and Management of Asthma. 2008
Coordinated by the NHLBI of the NIH
http//www.nhlbi.nih.gov/guidelines/asthma/asthgdl
n.htm
3
ASTHMA CASE

• 29 y/o male with h/o asthma
• 2 wks of coughing, SOB
• Albuterol nebs (3-4 x/d) and inhaler (3-4 x/d) at
  home for past wk
• Denies fever, chills, n/v, headache
• Asthma since 12 y with multiple ER visits (last 1
  y ago) hospitalizations (last 4 y ago)
• Thinks he has seasonal problems
• Nasal polyps removed several y ago
• Meds only albuterol prn as above
• Had been on fluticasone/salmeterol
• Cant afford stopped 2 y ago

4
ASTHMA-ASSOCIATED MORBIDITY/MORTALITY

• 32.6 million with asthma diagnosis in their
  lifetime
• 22.2 million currently diagnosed with asthma
• 12.2 million have asthma attacks annually
• 500,000 asthma-related hospitalizations/year
• gt 4000 deaths/year in US
• NEJM 073562083-91. NAEPP Guidelines 2007. Amer
  J Med 07120760-3

5
National Surveillance for Asthma US 1980-2004.
MMWR 200756(No. SS-8)
6
ASTHMA-ASSOCIATED MORBIDITY/MORTALITY

• 13.9 million office visits/year for adults
• 2 million ED visits/year
• 16 billion/year on treatment
• Mostly hospitalizations and ED for asthma
  exacerbations
• 80 of direct costs from 20 of patients who
  are difficult to control
• Millions of lost work and school days
• NEJM 073562083-91. NAEPP Guidelines 2007. Amer
  J Med 07120760-3

7
CONTROL OF ASTHMA

• Need for diagnosis and proper therapy
• NEJM 073562083-91. NAEPP Guidelines 2007. Amer
  J Med 07120760-
• Patient and physician have responsibilities in
  the management of severe asthma
• Patient responsibility
• Most common reason for poorly controlled asthma
  is nonadherence to treatment
• Medication must be taken as directed to be
  effective
• ADHERENCE
• Am J Med 07120760-3
• NEJM 073562083-91
• National Surveillance for Asthma US 1980-2004.
  MMWR 200756(No. SS-8)

8
Because no primary strategies for preventing
asthma have been identified, efforts to control
asthma exacerbations through interventions that
promote adhering to proper medical regimens and
reducing exposures to causes of asthma
exacerbations should continue to be pursued.
National Surveillance for Asthma US 1980-2004.
MMWR 200756(No. SS-8)
9
The Impact of Adherence
The consequences of poor adherence to therapies
are poor health outcomes and increased healthcare
costs
WHO. Adherence to Long-Term Strategies Evidence
for Action. 2003.
10
Patients Do Not See Asthmaas a Chronic Disease

• Survey of 198 adults hospitalized with asthma in
  an inner-city hospital
• 53 believed they only had asthma when they had
  symptoms no symptoms, no asthma
• More likely to say My asthma will be cured
• Lower adherence to ICS therapy
• 40 stated My lungs are always a bit inflamed
• More likely to use ICS when symptoms are absent
• Chest 06129573-80

11
Lung Function A Measure of Risk That Correlates
Inexactly With Symptoms

• Some patients have poor perception of airflow
  obstruction
• NAEPP Expert Panel Report 3 2007
• Airway obstruction measured by FEV1 does not
  directly correlate with patient-reported symptoms
• Chest 98113272-7
• Low FEV1 is a strong independent predictor of the
  need for acute care for asthma
• Chest 071321151-61

12
It is not uncommon to encounter patients who
report few symptoms but who have a severely
reduced FEV1 and only recognize the extent of
their impairment after treatment has relieved it
NAEPP Guidelines 2007
13
Perception of Illness and Adherence

• Likely to adhere to ICS
• Share medical view that asthma is a chronic
  disease with acute symptomatic flare-ups
• Likely to not adhere to ICS
• Do not think of asthma as a chronic disease with
  serious consequences
• Have episodic disease and dont think of asthma
  as a chronic disease
• Chest 0613065S-72S

14
Adherence to Medications

• Across disease states, rate of failure to fill
  initial prescription varies from 6-44
• WHO2003. http//www.who.int/chp/knowledge/publicat
  ions/adherence_full_report.pdf
• Long-term controller adherence rates
• ICS from 9-34
• LTRAs from 18-68
• J Asthma 2005135-40. 034093-101
• ICS/LABA about 22
• J Allergy Clin Immunol 06118899-904

15
Risk Factors for Life-Threatening Asthma and
Death from Asthma

• Long duration of asthma
• Poor control of asthma
• Systemic dependence on corticosteroids
• Noncompliance with medication regimen
• Psychosocial factors
• Poor socioeconomic conditions

• Inconsistent medical follow-up
• Delayed medical care
• Older age
• Cigarette smoking
• ASA sensitivity
• Prior hospitalization for asthma
• Prior use of mechanical ventilation

NEJM 073562083-91
16
HEALTHY PEOPLE 2010ASTHMA OBJECTIVES

• Reduce deaths
• Reduce hospitalizations
• Reduce ED visits
• Reduce activity limitations
• Reduce number of school or work days missed
• Increase number who receive formal patient
  education
• Increase number who receive appropriate asthma
  care according to the NAEPP guidelines
• Establish asthma surveillance system at least
  25 states
• DHHS. Respiratory Diseases Goal 24. In Healthy
  People 2010 (Conference ed., Vol II). Nov 2000

17
The clinical management of patients with asthma
remains complex, no matter how simple the
guidelines seem to make it.
Chest 031241196-8
18
National Asthma Educationand Prevention Program
(NAEPP)

• Stratification of patients according to severity
• Mild intermittent, mild persistent, moderate
  persistent, and severe persistent disease
• Initiate treatment based on severity
• Individual patients condition may change in
  severity
• Moderate to severe, etc
• All should avoid or control factors that trigger
  attacks
• All persistent asthma
• Should use daily controller medication to control
  airway inflammation
• As severity increases therapy should be increased

19
Asthma Assessment and MonitoringKey NAEPP
Updates

• Key elements of assessment and monitoring
• Severity
• Intrinsic intensity of underlying disease process
• Emphasized for initiating therapy
• Control
• Degree to which the parameters determining
  severity are minimized by therapeutic
  intervention
• Emphasized for monitoring and adjusting therapy
• NAEPP Guidelines 2007

20
Asthma Assessment and MonitoringKey NAEPP
Updates

• Ongoing assessment of control to adjust therapy
• Responsiveness and changes in severity over time
• Control Severity defined by
• Impairment
• e.g., effect on quality of life from symptoms
• Risk for future morbidity or impairment
• e.g., exacerbations and progressive loss of lung
  function
• NAEPP 2007

21
Asthma Severity and ControlImpairment Domain

• Symptoms
• Nighttime awakenings
• Need for SABAs
• Work/school missed
• Ability to engage in normal daily activities or
  desired activities
• Quality-of-life assessments

• Lung Function
• Spirometry
• Peak flow

Impairment Frequency and Intensity of Symptoms
and Functional Limitations
22
Asthma Severity and ControlRisk Domain

• Likelihood of
• Asthma exacerbations
• Progressive decline in lung function
• Risk of adverse effects from medications
• Assessment
• Frequency and severity of exacerbations
• Oral corticosteroid use
• Urgent-care visits or unscheduled asthma visits
• Lung function
• NAEPP Guidelines 2007

23
Goal of Asthma TherapyAchieve Control

• Reduce Impairment
• Prevent chronic troublesome symptoms (e.g.,
  cough or dyspnea)
• Require infrequent SABA ( 2 d/wk)
• Normal pulmonary function
• Normal activity levels
• Meet patients expectations of satisfaction
  with asthma care

• Reduce Risk
• Prevent recurrent exacerbations
• Minimize ED or hospitalizations
• Prevent progressive loss of lung function
• Therapy with little or no adverse effects
• NAEPP 2007

24
ASTHMA THERAPY

• Initial therapy
• Based on classification of asthma severity
• After therapy initiated, asthma control should be
  assessed regularly
• Determine if goals have been met
• Need for adjustment to therapy (ie, step up or
  step down)
• NAEPP Guidelines 2007

25
(No Transcript)
26
Quick-relief medications

• Short-acting ß2 agonists (SABAs)
• Albuterol, levalbuterol, etc.
• Therapy of choice for relief of acute symptoms
  and prevention of EIB (A)
• Systemic corticosteroids
• Moderate to severe exacerbations with SABAs to
  speed recovery and prevent recurrence of
  exacerbations (A)
• Anticholinergics Ipratropium
• Additive benefit to SABA in moderate to severe
  exacerbations (not FDA-approved)
• Alternative bronchodilator if do not tolerate SABA

27
Controller Medications

• Inhaled glucocorticosteroids (ICSs)
• Long-acting inhaled ß2-agonists (LABAs)
• Leukotriene modifiers (LTRAs)
• Systemic glucocorticosteroids
• Theophylline
• Cromones
• Omalizumab (Anti-IgE agent)

28
(No Transcript)
29
Every asthma care visit should include a
patient-centered assessment of their disease.
Amer J Med 07120760-3
30
ASSESSMENT AND CONTROL

• Patient control variability over time
• Assessment
• Should not rely on single time-point measures
• Should be based on multiple parameters at regular
  intervals
• e.g. 1- to 6-month intervals
• Eur Respir J 02201102-9
• NAEPP Guidelines 2007

31
(No Transcript)
32
CORTICOSTEROIDS

• Short courses oral gain prompt control
• Inhaled corticosteroids (ICSs) Long-term
  control of asthma
• Long-term oral severe persistent asthma
• NAEPP Guidelines 2007

33
ICS

• Most potent and consistently effective long-term
  control medication for asthma (A)
• Suppress but do not cure asthmatic inflammation
• Airway inflammation and airway hyperresponsiveness
  return to baseline about 2 wks after stopping
  ICS
• Well tolerated and safe at recommended dosages
  (A)
• Small risk of adverse events is well balanced by
  their efficacy (A).
• Risk increases with dose (B)
• virtually no clinically important, long-term
  adverse systemic effects are observed among
  adults taking low-to-medium doses.
• NAEPP Guidelines 2007. NEJM 093601002-14

34
REDUCING ICS ADVERSE EFFECTS

• Reduce local side effects (A)
• Oral candidiasis (thrush), Dysphonia, Reflex
  cough and bronchospasm
• Use spacers or valved holding chambers (VHCs)
  with MDIs
• No data on use with HFA MDIs
• Rinse mouth and spit after inhalation (B)
• Use lowest dose that maintains asthma control
• Evaluate patient adherence, inhaler technique,
  and environmental factors before increasing the
  dose (B)

35
ß2 AGONIST BRONCHODILATORS

• NO effect on late allergic response
• NOT an antiinflammatory agent
• NO effect on airway hyperresponsiveness
• Differences between agents
• Duration of action
• Selectivity for ß2 receptor

36
ß2 AGONISTS
Am J Med 071209(suppl)S6
37
(No Transcript)
38
ALBUTEROL MDIs

• FDA mandated no CFC-containing albuterol MDIs
  after December 31, 2008
• http//www.fda.gov/cder/mdi/albuterol.htm
• Tetrafluoroethane (HFA-134a) has replaced CFCs
• Additional cleaning and priming is necessary for
  HFA inhalers to prevent clogging
• 4 puffs (3 with ProAir) the first time they are
  used, and after 2 weeks of non-use (3 days with
  Xopenex HFA)

39
HFA ALBUTEROL INHALERS

• Equipotent to CFC-propelled inhalers
• Can be used with valved holding chambers
  (spacers)
• Bronchodilation comparable to nebulized albuterol
  when a sufficient number of puffs is administered
  and inhalational technique is good
• NEJM 093601002-14

40
ALBUTEROL MDIs

• Albuterol HFA MDI are all branded
• Earliest generic albuterol HFA MDI is 12/2010
• Now brand name co-pay
• Generic albuterol MDI had been lt 20
• Ventolin HFA 38 (has a counter)
• Proventil HFA 46
• ProAir HFA 42
• Xopenex (levalbuterol) HFA 52
• Drugstore.com 1/18/09. Medical Letter 085085

41
SHORT-ACTING ß2 AGONISTS USES

• Prevent exercise-induced asthma (EIA)
• Best agent
• Treatment of choice
• For mild intermittent asthma used as needed (prn)
• Acute exacerbation of asthma with systemic
  steroids

42
LONG-ACTING INHALED ß2 AGONISTS (LABAs)

• Salmeterol (Serevent) Powder for inhalation
• Formoterol (Foradil) Powder for inhalation
• Bronchodilation for gt 12 h Dosed q12h
• Indications
• Maintenance treatment of asthma
• Exercised induced asthma (EIA)
• Chronic obstructive pulmonary disease (COPD)

43
LABAs in Asthma

• Do not use as monotherapy
• No significant anti-inflammatory effects
• Added to ICS therapy
• Greater asthma control than either agent alone
• Of adjunctive therapies preferred treatment to
  combine with ICS in gt 12 y
• Not currently recommended to treat acute symptoms
  or exacerbations of asthma
• NAEPP Guidelines 2007

44
LABA WARNING

• FDA alert 11/05 Black Box Warning
• Any single LABA and LABA with ICS
• May increase the chance of severe asthma episodes
  and death
• Should not be 1st agent used and should not be
  used for acute asthma
• Medication guide will be given to patients when a
  prescription for a LABA is filled or refilled
• FDA Medwatch 9/18/05

45
LABA META-ANALYSIS

• For FDA Pulmonary-Allergy Drugs, Drug Safety and
  Risk Management and Pediatric Advisory Committees
• 110 RCT with 60,954 participants
• Placebo or active control
• Salmeterol, salmeterol/fluticasone, formoterol,
  and formoterol/budesonide
• SMART trial 43 of meta-analysis
• Available information 55 used ICS at baseline
• 65 used ICS during trial
• http//www.fda.gov/ohrms/dockets/ac/08/briefing/20
  08-4398b1-01-FDA.pdf

46
LABA META-ANALYSIS

• Asthma composite endpoint risk difference
• Asthma-related hospitalization, intubation, and
  death
• 2.8/1000 (95 CI 1.11-4.49)
• 20 asthma-related deaths
• 16 LABA vs. 4 non-LABA
• All with salmeterol
• http//www.fda.gov/ohrms/dockets/ac/08/briefing/20
  08-4398b1-01-FDA.pdf

47
LABA META-ANALYSISConclusions

• Associated with an increased risk of an
  asthma-related hospitalization, intubation, or
  death
• Greatest risk in 4-11 y
• No significant increased risk when LABAs were
  used with ICS
• http//www.fda.gov/ohrms/dockets/ac/08/briefing/20
  08-4398b1-01-FDA.pdf

48
FDA Advisory Committee Recommendations

• Remove the asthma indication from LABA agents
  (formoterol, salmeterol)
• Continue to approve the use of the combination
  LABA/ICS to treat asthma
• Fluticasone/salmeterol (Advair)
• Udesonide/formoterol (Symbicort)
• Doesnt apply to COPD
• http//www.acaai.org/public/linkpages/FDA_Hearing_
  Support_Med_121108.htm
• Await FDA decision

49
Drug Safety and Salmeterol The Controversy
Continues

• Ultimately, nearly all drugs have therapeutic
  windows within which physicians and patients must
  function.
• Like insulin and oral anticoagulation, LABAs
  have a narrow therapeutic window. They deserve
  the same caution and meticulous attention to
  detail that physicians expect of themselves when
  they prescribe potentially harmful drugs.
• Ann Intern Med 0814956-7. edit

50
INHALED STEROID PLUS LONG-ACTING ß2 AGONIST

• Fluticasone/Salmeterol DPI (Advair Diskus)
• 1 inhal q12h
• Fluticasone 100, 250 or 500 mcg/Salmeterol 50
  mcg/inhalation
• Fluticasone/Salmeterol MDI (Advair HFA)
• 2 inhal q12h
• Fluticasone 45, 115 or 230 mcg/Salmeterol 21
  mcg/inhalation
• Budesonide/Formoterol MDI (Symbicort)
• 2 inhal q12h
• Budesonide 80 or 160 mcg/Formoterol 4.5
  mcg/inhalation

51
ICS/LABA

• Add LABA if not well controlled on low- or
  medium-dose ICS
• Greater control than either agent alone
• Improves lung function
• Decreases symptoms and exacerbations
• Reduces use of SABA for quick relief
• J Allergy Clin Immunol 061173-16. NAEPP
  Guidelines 2007
• Not currently recommended to treat acute symptoms
  or exacerbations of asthma
• NAEPP Guidelines 2007

52
LABA

• Most studies did not use concurrent ICS or other
  controller meds
• Inadequate to determine whether controller
  medications would modify the risk for LABA
• ICS/LABA more effective than higher ICS dose
• Because of possibility of increased risk with
  LABA
• Use up to medium doses of ICS
• If not adequately controlled then ICS and LABA
  alternative choices at step 3
• NAEPP Guidelines 2007

53
Options to Reduce ICS BID Dose and Maintain
Control of Mild, Persistent Asthma

• May improve adherence to therapy
• ICS prn symptoms NOT FDA-APPROVED
• ICS/SABA prn symptoms NOT FDA-APPROVED
• ICS/LABA once daily plus SABAs prn symptoms NOT
  FDA-APPROVED
• LTRA orally once daily plus SABAs prn symptoms
• NEJM 053521519-28. 073562040-52.
  073562027-39
• Ann Intern Med 07147344-5. Editorial.

54
LEUKOTRIENE MODIFIERS

• Cysteinyl LT receptor antagonists (LTRAs)
• Zafirlukast (Accolate) 10 20 mg tabs 2 x/d
• Montelukast (Singulair) 10 mg tabs 4 5 mg
  chewable tabs once daily
• 5-lipoxygenase inhibitor
• Zileuton (Zyflo) 600 mg tabs 4 x/d
• Not used much
• Weaker bronchodilators than ß2 agonists and
  weaker antiinflammatory action than ICS

55
LTRAs

• Alternative, not preferred, treatment option for
  mild persistent asthma
• Monotherapy
• Modest improvement in lung function
• Obese, smokers, ASA sensitivity may have greater
  response
• NEJM 093601002-14
• Most outcome measures favor ICS LABA
• LABA as adjunctive therapy with ICS show
  significantly greater improvement in control
  measures than with LTRAs
• NAEPP Guidelines 2007

56
Individual patients and their physicians must
choose a treatment regimen that balances
efficacy with actual or perceived risks and
maximizes adherence.
No single approach will provide the best
combination of these factors for all patients
NEJM 073562027-39
57
Both the patient and the physician have
responsibilities in the management of severe
asthma. However, a major problem in the control
of asthma is that much of the responsibility lies
with the patient. for medication to be
effective, patients must take it regularly as it
is meant to be taken.
NEJM 073562083-91
58
QUALITY ASTHMA CARE

• Establish asthma diagnosis Rule out other
  conditions
• Classify severity of asthma
• Routine follow-up care
• Every 1-6 mon
• Spirometry every 1-2 y unless unstable
• Review asthma action plan
• Assess for referral to specialty care Know when
  to refer

59
QUALITY ASTHMA CARE

• Control asthma triggers
• No smoking
• Avoid environmental and occupational triggers
• Treat or prevent co-morbid conditions
• Rhinosinusitis
• Vocal cord dysfunction
• GERD, COPD, influenza vaccine
• Prescribe medications according to severity

60
QUALITY ASTHMA CARE

• Monitor use of SABAs
• gt 1 Albuterol MDI/mon is cause for alarm
• Written asthma action plan Reduces mortality
• Provide education on patient self-management
• Repetition key to learning
• Emphasize environmental controls, inhaler
  techniques, pharmacotherapy
• Written asthma action plan
• Am J Med 07120760-3