MANAGEMENT OF ACUTE ASTHMA AND C.O.P.D

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MANAGEMENT OF ACUTE ASTHMA AND C.O.P.D Powered By Docstoc
					      UPDATE ON COPD & ASTHMA




               DR DINESH SARALAYA
                    MD FRCP
       CONSULTANT RESPIRATORY PHYSICIAN
BRADFORD TEACHING HOSPITALS NHS FOUNDATION TRUST
                          Definition of COPD
                                  COPD is a preventable and treatable
                                  disease state characterised by airflow
                                  limitation that is not fully reversible1

                                  The airflow limitation is usually
                                  progressive and is associated with an
                                  abnormal inflammatory response of
                                  the lungs to noxious particles or
                                  gases, primarily caused by cigarette
                                  smoking1

                                  Although COPD affects the lungs, it
                                  also produces significant systemic
                                  consequences1
                                  CSIS: CHRONIC SYSTEMIC INFLAMMATORY
                                  SYNDROME

ATS/ERS Guidelines 2004
                                                                  1. ATS/ERS 2004
Risk Factors for COPD

                    Nutrition

                    Infections

                Socio-economic
                status




Aging Populations                3
                   Pathogenesis of COPD
         Cigarette smoke
           Biomass particles
              Particulates
                                       Host factors
                                  Amplifying mechanisms



                    LUNG INFLAMMATION
Anti-oxidants                              Anti-proteinases


     Oxidative
      stress                          Proteinases

                                            Repair
                                          mechanisms

                 COPD PATHOLOGY            Source: Peter J. Barnes,
                                           MD
        Changes in Small Airways in COPD Patients




                             Inflammatory exudate in lumen




                                   Disrupted alveolar attachments

                              Thickened wall with inflammatory cells
                              - macrophages, CD8+ cells, fibroblasts

                               Peribronchial fibrosis
Lymphoid
 follicle

                                            Source: Peter J. Barnes,
                                            MD
Changes in the Lung Parenchyma in COPD




                              Alveolar wall destruction




                                Loss of elasticity

                               Destruction of pulmonary
                               capillary bed

                           ↑ Inflammatory cells
                            macrophages, CD8+ lymphocyte


                                 Source: Peter J. Barnes,
                                 MD
                          Air trapping in COPD
          Normal                                           Severe
                               Mild/moderat                COPD
Inspiration                          e
                                  COPD
   small
   airway



   alveolar attachments       loss of elasticity   loss of alveolar
                                                   attachments
Expiration


                                                                      closure




   ↓ Health             Dyspnea                        Air trapping
    status         ↓ Exercise capacity                Hyperinflation
                                                            Source: Peter J. Barnes,
                 COPD - Statistics

   Most common respiratory disease in the UK
   Currently 4th leading cause of death, rising to 3rd by 2030
   Prevalence ~ 1%, 900,000 diagnosed cases in UK (2007)
   Estimated true prevalence ~6% due to non-presentation
    and misdiagnosis
   Prevalence estimated to be 13.3% in people >35 years of
    age
   Prevalence in women is increasing


                                                       Facts about COPD. Department of Health
                      http://www.dh.gov.uk/en/Healthcare/Longtermconditions/COPD/DH_113006
             Summary of COPD Statistics http://www.hse.gov.uk/statistics/causdis/copd/index.htm
                   COPD - Statistics
   70% of patients have mild-moderate disease at diagnosis

   Co-morbidities:
     • 50% hypertensive

     • 33% asthmatic

     • 36% obese (BMI > 25)



   £800m direct healthcare costs – double cost of asthma (2007)

   COPD accounts for 10% of all hospital admissions

   10% of COPD patients die within 3 months of admission

   In UK 25,000 – 30,000 deaths per year (2007)

                                                         Facts about COPD. Department of Health
                        http://www.dh.gov.uk/en/Healthcare/Longtermconditions/COPD/DH_113006
               Summary of COPD Statistics http://www.hse.gov.uk/statistics/causdis/copd/index.htm
                               Model of Annual Decline in FEV1
                       100                                               Never smoked or
FEV1 (% of value at age 25)



                                                                         not susceptible to
                                                                               smoke
                              75
                                        Smoked regularly &                  Stopped at 45
                                         susceptible to its
                              50             effects

                                   Disability
                                                                                     Stopped at 65
                              25

                                   Death

                              O
                                   25                      50                                  75
                                                        Age (years)
                                                                      Modified from Fletcher and Peto
   AIRFLOW OBSTRUCTION IS THE KEY IN
                COPD
Airflow obstruction is
defined as:

•a reduced FEV1 ( forced
expiratory volume in 1 second)

•a reduced FEV1/FVC
ratio(where FVC is Vital capacity)
such that the FEV1 is less than
80% predicted and the
FEV1/FVC is less than 0.7

The airflow obstruction is due to a
combination of airway and
parenchymal damage.
     Diagnosis of COPD
                       EXPOSURE TO RISK
   SYMPTOMS                FACTORS
     cough                    tobacco
    sputum                  occupation
shortness of breath
                      indoor/outdoor pollution
                 


             SPIROMETRY
Long-term trials in COPD
                                                                 Short acting anticholinergics

                                                                 Inhaled Corticosteroids (ICS)

                                                                       N-Acetylcysteine
  LHS1 -1994
  Ipratropium                                                   Long Acting Beta2 Agonists/ICS


          EUROSCOP-1999      ISOLDE-2000                              L.A.M.A.
            Budesonide        Fluticasone
                                             BRONCUS -2005
                                             N-Acetylcysteine

                CCLS-1999     LHS II-2000             TORCH -2007
                Budesonide   Triamcinolone             SALM + FP


                                             SWFRANSKI          INSPIRE-2007
                               CALVERLEY                         SALM + FP
                                                                 v tiotropium



1994                                                                            2008




                                                                                UPLIFT
Addressing disease progression in COPD
– a key treatment goal

• COPD is a preventable and treatable disease state
  characterised by airflow limitation that is not fully
  reversible2,3

• COPD management has traditionally concentrated
  on the reduction and control of symptoms
                                       Hypothesis for UPLIFT
                • 1-year rate of decline in FEV1 for tiotropium plus usual care† versus
                  placebo plus usual care from post-hoc analysis of two 1-year studies




*p=0.035 tiotropium versus placebo (mean regression slopes)
† Usual   care excluded long-acting beta-agonists and anticholinergics



Adapted from Anzueto et al. Pulm Pharm & Therap. 2005; 18:75-815
Largest cohort of patients with mild COPD to
                    date1
                             Tiotropium (n = 2986)   Control (n = 3006)

                    60

                    50

                    40
       Percentage


                    30

                    20

                    10

                     0
                         NICE Mild      NICE Moderate         NICE Severe




                                     70-80%
                                     50-80%
                                     30-50%
                                      ≤30%
              The rate of decline in FEV1 was not altered vs. control
                          Mean values at each time point

              1.50                                                    Tiotropium                   Control
                      *          *
                                            *
              1.40                                       *
                                                                      *
                                                                                  *                                                  Post-Bronch FEV1
                                                                                              *                                            = 47 – 65 mL
                                                                                                          *
   FEV1 (L)




              1.30                                                                                                        *   (n=2516)
                      *          *          *
                                                         *                                                                    (n=2374)
              1.20                                                    *          *            *           *               *
              1.10                                                                                                            (n=2494)
                                                                                                                                         Pre-Bronch FEV1
                                                                                                                              (n=2363)     = 87 – 103 mL
              1.00
                 0
                     01          6         12           18           24          30           36           42             48
                    Day 30
                (steady state)                                      Months
Adapted from Tashkin DP, Celli B, Senn S et al for the UPLIFT Study Investigators.
N Eng J Med 2008: 359(Suppl 15):1543-1554.
 *P<0.001 vs. control. Repeated measure ANOVA was used to estimate means. Means are adjusted for baseline measurements.
 Baseline trough FEV1 (observed mean) = 1.116 (trough), 1.347 (peak).
 Patients with ≥3 acceptable PFTs after day 30 were included in the analysis.
             Significantly reduced time to first
            exacerbation compared to control1


                             Tiotropium (N=2986)       Control         ∆ Contol –
                                                      (N=3006)         Tiotropium
                              Median (95% CI)      Median (95% CI)      (months)


        Median time to
        first exacerbation
        (month)               16.7 (14.9, 17.9)    12.5 (11.5, 13.8)      -4.2




               33% delay in time to first exacerbation = 4.2 months


p < 0.001
              Onbrez Breezhaler – Indication

   Indacaterol is a Long-Acting Beta2 Agonist (LABA) indicated for
    maintenance bronchodilator treatment of airflow obstruction in adult
    patients with chronic obstructive pulmonary disease (COPD)

   The recommended dose is one 150 microgram capsule once a day,
    using the Onbrez Breezhaler inhaler. The dose should only be increased
    on medical advice

   One 300 microgram capsule once a day, using the Onbrez Breezhaler
    inhaler has been shown to provide additional clinical benefit with regard
    to breathlessness. The maximum dose is 300 microgram once daily

   Onbrez Breezhaler should not be used in asthma due to the absence of
    long-term outcome data in asthma




                              Onbrez Breezhaler Summary of Product Characteristics
            Indacaterol shows rapid bronchodilation
                        within 5 minutes

                       Indacaterol 150µg od    Salbutamol     Salmeterol & Fluticasone       Placebo

            1.60

            1.55
                        †            ***                                                             ***
            1.50
              ††
 FEV1 (L)




                       ***                             ***
            1.45
              ***
            1.40

            1.35

            1.30
                   0            20            40         60            80             100              120
                                                      Time (min)


         Data are least squares means
Treatment differences: ***p<0.001 vs placebo; ;
 †p<0.01, ††p<0.01 vs salmeterol & fluticasone




               N.B. Indacaterol is not licensed for acute symptomatic relief
                                                                            Balint et al. Poster presented at
                                                                                ERS Annual Congress 2009
               INVOLVE: 52-week efficacy and safety
                         Study Design
      Double-blind, randomized, placebo-controlled, parallel-group
                                 study
                 in male and female patients with COPD

                                            Indacaterol 300 μg od n=437

                                            Indacaterol 600 μg od n=428
                 n=2446
       Screening period                       Placebo                       n=432

                                            Formoterol 12 μg bid n=435



               2 weeks          Baseline             52 weeks

Please note indacaterol 600mcg is not a
licensed dose. Licensed doses are 150 and                   Dahl et al Thorax 2010, 65: 473-379
                                 Indacaterol demonstrates sustained
                                  efficacy over 1 year vs formoterol

                                     Placebo          Formoterol 12µg bd       Indacaterol 300µg bd      Indacaterol 600µg bd

                                                   *** ***
                                                    †
                                                       †††                          *** ***
                                                                                     ††† †††                        *** ***
                                                                                                                     ††† †††
                              1.60          ***    1.45 1.49                 ***    1.48 1.48
                                     1.31
                                            1.43
                                                                      1.31
                                                                             1.38                             *
                                                                                                             1.32
                                                                                                                    1.43 1.43
                              1.40                                                                    1.29
     Trough FEV1 (L) at 24h




                              1.20
                              1.00
                              0.80
                              0.60
                              0.40
                              0.20
                              0.00
                                             Day 2                           Week 12                         Week 52
                                                                      (primary endpoint)
    Data are least square means
    Treatment differences: *p<0.05, ***p<0.001 vs placebo;
    †p<0.05, †††p<0.001 vs formoterol

Please note indacaterol 600mcg is not a
licensed dose. Licensed doses are 150 and
300mcg.                                                                                         Dahl et al Thorax 2010, 65: 473-479
                  Indacaterol provides significant and clinically relevant improvements
                                     in breathlessness over 1 year


                                                                        ††
                  3.0                                                                         ***
                                               †                        ***
                                              ***                                       **

                                   ***                          ***
TDI focal score




                                                                              1 point
                  2.0
                         1 point                    1 point




                  1.0




                   0
                                         12                     24                           52
                                                            Weeks

     ***p<0.001, **p<0.01 vs placebo; †p<0.05, ††p<0.01 vs formoterol
      TDI captures change from baseline at each visit. Change of ≥1
      in TDI score = clinically important improvement. Data are LSM

                                                                                   Buhl et al. ERS 2009
              Breezhaler – single dose dry powder inhaler

Onbrez is delivered in a new, proprietary dry-powder device known as the
Breezhaler®. This inhaler has been designed to be robust, compact and
straightforward to use by patients.




The Breezhaler is a single-dose dry powder inhaler:
one capsule must be inserted per inhalation.
                           ICS/LABA: reduced risk of
          rehospitalisation or death (UK patients)
                               ICS/LABA               ICS                LABA
  Risk of             0
  rehospitalisation
  or death vs        -5
  reference
                    -10
  patients (%)
                                                                           - 10%
                    -15

                     -20                              - 16%*
                     -25
                                                                   n = 3636
                     -30

                     -35

                     -40
                                                        * p<0.05 vs reference patients
                     -45          - 41%*

     Retrospective cohort analysis of COPD-related rehospitalisations or deaths within 1 year of
     first hospitalisation in 3636 COPD patients receiving ICS and/or LABA compared with 627
     reference patients receiving short-acting β2-agonists alone (UK General Practice Research
     Database )
Soriano JB, et al. Am J Respir Med 2003;2:67–74
    RELIEF OF BREATHLESSNESS IS A KEY AIM
•  Clinically significant improvements in breathlessness (Transition
Dyspnoea Index, TDI >1) were seen         with Seretide within 1 week of
treatment1-3
                                                  Sustained improvement in breathlessness over 6 months1,2
                                                    2
                Improvement in breathlessness
                 (Transition Dyspnoea Index)


                                                  1.5                                                                        1.7*


                                                    1
                                                        Threshold beyond which patients can feel a difference 3
                                                                                                                   0.9
                                                  0.5                                                      0.9

                                                                   0.4                      0.4
                                                    0
                                                                 0.4                  0.4


                                                              Placebo            Salmeterol           Fluticasone           Seretide
                                                                                 50 µg b.d.           500 µg b.d.        50/500 µg b.d.

                                                All patients FEV1 <50% and received as required salbutamol and could be maintained on regular theophylline.
•                                               *p=0.003 vs salmeterol and placebo, p=0.08 vs fluticasone.


    Seretide is indicated for the treatment of symptomatic patients (FEV1
    <50% predicted) with a history of repeated exacerbations, who have
        significant symptoms despite regular bronchodilator therapy.

                                                                                                                                        1. Mahler DA et al. Am J Respir Crit Care Med 2002; 166: 1084-1091
                                                                                                                                                    2. Data on file. GlaxoSmithKline SFCA3006, FEV1 <50%
                                                                                                                                              3. Witek TJ and Mahler DA. J Clin Epidemiol 2003; 56: 248-255
                                                                                                                  4. Brusasco V et al. Thorax 2003; 58: 399-404 5. Donohue J et al. Chest 2002; 122: 47-55
                                    SGRQ total score

        Adjusted mean change SGRQ total score (units)
         3
           2                                                                                                Placebo

           1                                                                                  *             SALM
           0                                                                                      †         FP
         –1                                                                                       ††        SALM/FP
         –2
         –3
                                                                                                       A change in
         –4                                                                                            score of 4 units is
         –5                                                                                            a clinically
                 0         24         48      72     96                   120             156          meaningful result
                                           Time (weeks)                                                for patients with
 Number of 1149            854       781              726       675        635            569          respiratory
 subjects  1148            906       844              807       723        701            634          disease
           1155            942       848              807       751        686            629
           1133            941       873              814       773        731            681
                                                                                          Calverley et al. NEJM 2007
*p = 0.057 vs placebo; †p < 0.001 vs placebo;   ††p   < 0.001 vs placebo, SALM and FP; vertical bars are standard errors
                                           HO Pop Source Figure: 7.3.004                                           34
                   Post-bronchodilator FEV1
           Adjusted mean change FEV1 (mL)
           100

            50

             0
                                                                                       *†
           –50
                                                                                   *
         –100                                                                  *

                       Placebo       SALM          FP      SALM/FP
         –150
                   0        24       48        72     96       120           156
                                           Time (weeks)
     Number of 1524       1248      1128      1049       979    906            819
     subjects  1521       1317      1218      1127      1054   1012            934
               1534       1346      1230      1157      1078   1006            908
               1533       1375      1281      1180      1139   1073            975
*p < 0.001 vs placebo; †p < 0.001 vs SALM and FP                  Calverley et al. NEJM 2007
       Rate of exacerbations requiring systemic
           corticosteroids over three years
            Mean number of exacerbations/year
            1.2
              1                          43% reduction
                       0.80
            0.8
                                       0.64*
            0.6                                        0.52*
                                                                0.46*†‡
            0.4
            0.2
              0
                     Placebo           SALM              FP    SALM/FP
                                               Treatment
*p < 0.001 vs placebo; †p < 0.001 vs SALM; ‡p = 0.017 vs FP    Calverley et al. NEJM 2007
                Formoterol has a significantly faster onset of action than salmeterol in
                COPD1


                                                                          Formoterol 12µg
                                   n=270                                  Salmeterol 50µg                    * p=0.022; † p=0.001
                          0.20                                          †
Change from baseline in




                          0.15         *


                          0.10
FEV1, L




                          0.05


                            0
                           5 minutes                     30 minutes                             60 minutes

                                                          Time Postdose


                                           1. Cote C. et al. Faster onset of action of formoterol vs. Salmeterol in patients with COPD:
                                           A multicentre, randomized study. Pulmonary Pharmacology & Therapeutics 22 (2009) 44-49
   Symbicort significantly reduces the rate of exacerbations
   needing medical intervention


                                                            Szafranski                                    Calverley
                                                Symbicort    Budesonide    Formoterol         Symbicort   Budesonide    Formoterol
                                                                                         5                                 +3%

                                           0                                             0
   Rate of exacerbations vs placebo (%)




                                                                             -2%
                                           -5                                            -5


                                          -10                                           -10

                                                                                                             -12%
                                          -15                                           -15
                                                               -15%

                                          -20                                           -20                Symbicort
                                                              Symbicort
                                                                  vs                                           vs
                                                              formoterol                                   formoterol
                                          -25                                           -25     -24%*       p=0.015
                                                 -24%*         p=0.043

                                          -30                                           -30

Szafranski W, et al. Eur Respir J 2003;21:74–81
Calverley PM, et al. Eur Respir J 2003;22:912–919                                                            *p<0.05 vs placebo
                                                       CLIMB:
                                                    Study design
 Multicentre study with a randomised, double-blind, active controlled, parallel group design to assess the efficacy
 of Budesonide/Formoterol as an add-on treatment to tiotropium in patients with severe COPD.

         n = 660

  Run-in                       Tiotropium 18µg od + Bud/Form 400/12µg bd
                                                                                                                                 (n=329)
Tiotropium
18µg od                R
No ICS or
LABA                           Tiotropium 18µg od + Placebo
                                                                                                                                 (n=331)

Visit:    1   2            3                  4                                         5                                                    6
Week:         –2           0                  1                                         6                                                    12

                                  Reliever: terbutaline 0.5mg used


 Bud/Form = budesonide/formoterol
 Tio = tiotropium
                                Adapted from Welte T, Miravitlles M, Peterson S, et al. Efficacy and tolerability of budesonide/formoterol
                                added to tiotropium in COPD. Am J Resp Care Med 2009; 180:741-750
                                 CLIMB:
                                 Tio + Bud/Form improves clinic lung function variables vs. Tio alone1

                                        P < 0.001
                                 12                                      Pre-dose
                                             P < 0.001                                                               Treatment difference* (95% CI)
                                                                          5 min post-dose                            (change in Tio + Bud/Form vs. Tio
                                                                                                                                                                       P-value
                                 10                                                                                  + placebo)
                                                                          60 min post-dose
                                                                                                         FEV1* (L)

                                  8                         P < 0.001                                           Pre-dose                1.06 (1.04–1.09)              < 0.001
  Percentage improvement with




                                                                P < 0.001                                       5 min post-dose         1.11 (1.09–1.13)              < 0.001
  Tio + Bud/Form vs. Tio alone




                                      P < 0.001                                                                 60 min post-dose        1.11 (1.09–1.14)              < 0.001
                                  6                                                                      FVC* (L)
                                                                                       P < 0.001
                                                                                                                Pre-dose                1.03 (1.00–1.05)                0.021
                                                                                                                5 min post-dose         1.07 (1.05–1.09)              < 0.001
                                  4
                                                         P = 0.021           P = 0.020                          60 min post-dose        1.07 (1.05–1.09)              < 0.001

                                                                                                         IC* (L)
                                  2                                                                             Pre-dose                1.03 (1.01–1.06)                0.020
                                                                                                                60 min post-dose        1.05 (1.03–1.08)              < 0.001
                                                                                         N/A




                                  0
                                             FEV1                FVC                     IC

* Change expressed as ratio between means over treatment period and visit 3 value (Multiplicative ANOVA)
CI = confidence intervals
                                                            1. Adapted from Welte T, Miravitlles M, Peterson S, et al. Efficacy and tolerability of budesonide/formoterol
                                                            added to tiotropium in COPD. Am J Resp Care Med 2009; 180:741-750
   CLIMB:
   Tio + Bud/Form improves overall health status vs. Tio alone1


                                                  –6.00
                                                                                                   Tio + Bud/Form
                                                  –5.00

                    Adjusted mean difference in
                                                                                                   Tio + placebo
                                                                    -3.8
                                                  –4.00

                                                  –3.00
                    SGRQ-C score


                                                  –2.00                         -1.5

                                                  –1.00

                                                  0.00

                                                             SGRQ-C TOTAL


SGRQ-C treatment comparisons from randomisation to last visit
SGRQ-C variable              Treatment                                                 Mean diff.       95% CL                  P-value
TOTAL                        Tio + Bud/Form vs. Tio + placebo                          –2.27            -4.23, -0.318           0.023




                                     1. Adapted Welte T, Miravitlles M, Peterson S, et al. Efficacy and tolerability of budesonide/formoterol
                                        ANOVA
                                     added to tiotropium in COPD. Am J Resp Care Med 2009; 180:741-750
CLIMB:
Mean number of severe exacerbations

                                 0.4
                                             62% reduction in rate of exacerbation*
                                                                                                                                      Tio + Bud/Form
                                                                                                                                      Tio + placebo
         Exacerbations/patient


                                 0.3         Ratio: 0.38 (95% CI: 0.25–0.57)
                                             P < 0.001
                                                                        Poisson regression


                                 0.2



                                 0.1




                                 0.0
                                       0          15               30              45              60              75              90
                                                            Days since randomisation
                                       * Severe exacerbations defined as oral steroid use, ER visits and
                                       hospitalisations


                                           1. Welte T, Miravitlles M, Peterson S, et al. Efficacy and tolerability of budesonide/formoterol
                                           added to tiotropium in COPD. Am J Resp Care Med 2009; 180:741-750
New NICE Guidelines – June 2010




                     NICE Clinical Guideline CG101 – June 2010
                 Bronchial Asthma
Asthma is derived from the Greek word “ ASTHMAINO” : Breathless &
wheeze

“ A condition with widespread narrowing of the bronchial airways which
changes in severity over short periods of time either spontaneously or
by treatment ”

Thorax 1959; 14: 286

A chronic inflammatory disorder of the airways in which
many cells play a role, including mast cells and eosinophils in
susceptible individuals this causes symptoms which are usually
associated with widespread airflow obstruction that is often reversible
either spontaneously or with treatment and causes increased airway
responsiveness to a variety of
stimuli

Eur Respir J 1992;5: 501
    Number of people living with asthma in the
                   UK today
                                                                                                           12
            Data includes 590,000 teenagers                                                        11               1
            and 700,000 people over 651                                                      10                            2
                                                      Total                                 9                                 3
                                                   5.2 million1
                                                                                              8                           4
                                                                                                    7                5
                                                                                                            6


                                  Women
                 Men            2.9 million1
             2.3 million1




                                                                              Every 6 hours someone dies from asthma.2

1. Where Do We Stand? Asthma in the UK Today. Published December 2004. Available at: http://www.asthma.org.uk/how_we_help [Accessed
October 2006.]. 2. General Register Office collated in Office for National Statistics mortality statistics for England and Wales; General Register
Office for Scotland; General Register Office for Northern Ireland collated by the Northern Ireland Statistics & Research Agency (2004).
                  Asthma hospitalisation and
                 mortality remains high in the UK

       More than 1,400 people die from asthma each
        year

       71,000 hospital admissions for asthma every year

       For every two people admitted to hospital for
        asthma, five others are treated in Accident and
        Emergency

Asthma UK 2004. Living on a Knife Edge. Available at
http://www.asthma.org.uk/health_professionals/ordering_materials/living_on_a.html. Last accessed 25 January 2007.
            Asthma deaths occur across disease
                        severity1,2

    It is a myth that only severe                                                                            Number of asthma deaths across
                                                                                            100
     asthma can prove fatal                                                                                       disease severity 2001–2003




                                                                                Number of deaths
                                                                                                   75

    Asthma deaths occur across
                                                                                                   50   52%
     disease severity with deaths
     occurring in those patients                                                                   25
                                                                                                                   21%
     whose asthma is considered                                                                                                 16%             11%
     mild-to-moderate                                                                              0
                                                                                                        Severe   Moderately      Mild        Unknown
                                                                                                                   severe

                                                                                                                  Asthma severity (%)          n=57



1. Burr ML, Davies, BH, Hoare A, et al. A confidential inquiry into asthma deaths in Wales. Thorax 1999; 54; 985-9. 2. Harrison B, Stephenson P,
Mohan G, Nasser S. An ongoing confidential enquiry into asthma deaths in the eastern region of the UK, 2001–2003. Prim Care Respir J 2005 Dec; 14: 303–
13.
Summary of the allergic inflammatory cascade
   in patients with IgE-mediated asthma

            B lymphocyte                   Allergic
                                       inflammation:
                      Allergic        eosinophils and
-switch             mediators          lymphocytes


           Plasma cell


Release                               Allergens
 of IgE                                           Asthma exacerbation




                                 Mast cells
                                 Basophils
               Diagnosis of Asthma
SYMPTOMS: Episodic/ Variable
•Wheeze
•Shortness of breath
•Chest tightness
•Cough

These tend to be:
•Variable
•Intermittent
•Worse at night
•Provoked by triggers

When cough is the predominant
symptom without wheeze, this is
often referred to as
“COUGH VARIANT ASTHMA”
          Features that increase the
        probability of asthma in adults
   >1 of the following: wheeze, breathlessness, chest
    tightness, cough, particularly if:

       worse at night and early morning
       in response to exercise, allergen exposure and cold air
       after taking aspirin or beta blockers
       Personal/family history of asthma/atopy


   Widespread wheeze heard on auscultation of the chest
   Unexplained low FEV1 or PEF
   Unexplained peripheral blood eosinophilia
  HOW DO WE ASSESS ASTHMA
         CONTROL?
•Minimal symptoms in the day or night

•Minimal need for reliever

•No exacerbations

•No limitations in physical activity

•Normal lung function ( early morning PFR > 80% of
 predicted or best)

BTS ASTHMA GUIDELINES APRIL 2007
ASTHMA CONTROL TEST
  FACTORS PREDICTING ASTHMA
          SEVERITY

•SEX

•AGE

•POLLEN ALLERGY

•LACK OF COMPLIANCE TO TREATMENT

•SMOKING

Bjorn Stallberg. Resp Med 2007;101; 2076-83
BTS ASTHMA GUIDELINES 2008
          Combination vs. Separates?
NICE recommends use of combination therapy as an option where
both ICS and LABA are appropriate

   Combination therapy is at least as clinically effective as the ICS plus LABA
    components in separate inhalers

   Single combination device is associated with significantly improved adherence and
    prevents the patient from taking the LABA alone

   The decision between a combination inhaler or ICS plus LABA in separate inhalers
    should be made on an individual basis, considering likelihood of adherence and
    therapeutic need

   Use of a single combined inhaler decreases the prescription cost for the individual

   When an ICS + LABA treatment is appropriate, the least costly delivery method should
    be used, which is currently a combination device
COMBINATION INHALERS
Check inhaler technique
                          Severe Asthma
The majority of asthmatics have mild to moderate disease and achieve
reasonable asthma control by regular use of ICS and bronchodilators .

However a small subset of asthmatic patients remain symptomatic and suffer
from frequent exacerbations or persistent airflow limitation despite use of
high doses of inhaled steroids ( about 10% of asthmatics).

These patients are often labelled as:
•Severe asthma
•Difficult to treat asthma
•Therapy resistant asthma
•Steroid – dependant asthma

Severe asthma is a frustrating disease for both patients &clinicians treating
them.

These patients are difficult to treat , are prone to severe exacerbations and
contribute disproportionately to the overall cost of asthma.
    ATS WORKSHOP CONSENSUS FOR DEFINITION OF SEVERE /
               REFRACTORY ASTHMA :2000
Major Criteria                     Minor criteria

Use of oral steroids for           Requirement for daily treatment with
>50% of the time                   Theophylline, LTA


Continuous use of high dose                  Daily asthma symptoms requiring
rescue Rx
ICS ( > 1200 mcg
of Beclomethasone or equivalent)   Persistent airflow obstruction
                                   ( FEV1 < 80%) PEF variability >20%

                                   >1 urgent care visit for asthma
                                            in last year

                                   >3 oral steroid bursts in last year

                                   Near fatal asthma in last year

                                   Prompt deterioration with < 25 % reduction in
                                   ICS dose

DEFINITION REQUIRES ONE OR BOTH MAJOR AND ATLEAST 2 MINOR CRITERIA
      TREATMENT OPTIONS IN SEVERE
           ALLERGIC ASTHMA
•Patients with severe persistent asthma often require multiple
therapies, including high-dose inhaled corticosteroids (ICS) and
long-acting β2-agonists (LABA) combinations.

• Despite the use of these medications, patients can remain
inadequately controlled due to persistent airway inflammation
[Bateman et al. 2004; Niven et al. 2008].

•Omalizumab (XOLAIR®, Novartis Pharma AG, Basel, Switzerland)
is a recombinant humanized monoclonal anti-immunoglobulin E
(IgE) antibody approved in the European Union as an add-on
therapy for the treatment of patients (≥6 years) with severe
persistent allergic (IgE-mediated) asthma, that remains
uncontrolled despite treatment with high-dose ICS and a LABA
[XOLAIR SmPC 2009].
      Omalizumab anti-IgE monoclonal
                antibody
   5% murine derived component

   Binds circulating free IgE

   Prevents IgE binding to high-
    and low-affinity receptors

   Minimal risk of anaphylaxis

   Forms small, biologically inert
    omalizumab:IgE complexes

   Non-complement fixing antibody
      Allergens and mast cells

         Allergen




                             IgE

C3           Binding site
                                   FcRI

                                     Mast cell
    The allergic cascade is stopped by
                omalizumab
                                    omalizumab complexes
                                         with free IgE
 Allergen-driven
B-cell secretes IgE




              IgE
                                                                              FcRI

                                    Omalizumab
                                                                                           Mast cell
                      Omazilumab binds to circulating IgE regardless of the antigen specificity
     B-cell           Forming small biologically inert IgE – anti IgE complexes.

                      There is a 90-99% reduction in free serum IgE soon after administration
                      Of Omazilumab.

                      These low levels persist throughout treatment with appropriate doses.
 Omalizumab mechanism of action
          B lymphocyte
                                        Reduces          Allergic
                                        mediator     inflammation:
                                                    eosinophils and
                                         release      lymphocytes
    -switch                 Allergic
                            mediators                             Reduces
                                                                   allergic
           Plasma cell                                          inflammation

Release        omalizumab
 of IgE
                                                 Allergens

                                                                      Exacerbation
                                 Reduces                          Prevents asthma
   Binds to free IgE,          high-affinity                     exacerbations and
       reducing                 receptors                        reduces symptoms
    cell-bound IgE
                                    Mast cells
                                    Basophils
                                   Eosinophils
     Omalizumab expanded dose table – this one table applies to
                  paeds, adolescents and adults




66
                  OMALIZUMAB: BTS
Omalizumab is a humanised IgE monoclonal antibody which
binds to
circulating IgE.

In the UK it is licensed in adults and children >12 yrs with asthma
with
the following indications:

1.Patients on high dose ICS and LABA

2.With impaired lung function

3.Patients who are symptomatic with repeated exacerbation

4.Those who allergy as a major cause of their asthma
                   Patients eligible for Xolair treatment

     >12 years                                                           FEV1 <80%
     severe persistent allergic asthma                                   frequent daytime symptoms or night-time
     positive skin test or in vitro reactivity to a perennial             awakenings
      aeroallergen                                                        multiple documented severe asthma
     convincing IgE mediated asthma                                       exacerbations




                                                                 + + +
              Daily high-dose inhaled corticosteroids, plus a long-acting inhaled beta2-
              agonist

Smoking              Trial & documented compliance with leukotriene receptor
cessation            antagonists, theophyllines, oral corticosteroids and beta2 agonist
                     tablets




 >3 severe exacerbations of asthma                                         >2 severe exacerbations
 within the previous year                                                  of asthma requiring
   • >1 requiring hospital admission                              OR       hospital admission within
   • +2 requiring treatment/monitoring in                                  the previous year
     excess of patient’s usual regimen,
     in
    69 A&E
OMALIZUMAB THERAPY IN BRADFORD
Bradford population 480,000

About 850 asthma admissions every year

101 ICU asthma admissions in 2005

Huge drain on health resource

Developed difficult asthma clinic in Bradford in 2004

Set up Omalizumab service in March 2006 : 1st patient

We currently have 25 patients on treatment.

Treatment has been stopped in 1 patient

Funding approved by PCT in about 2 weeks following a signed
form

Patient focus group in November 2009
 Real-life effectiveness of Omalizumab in
patients with severe asthma in a single UK
                   hospital
 A.Simmons, K. Regan, A.Aziz, D Saralaya

 American Thoracic Society, New Orleans May 2010
                            METHODS
•Patients included in the audit were receiving omalizumab
(150–375 mg q4wk or q2wk) for severe allergic asthma at the Bradford
Royal Infirmary, Bradford, UK.

Outcomes evaluated included

•hospital admissions
•accident and emergency (A&E) visits
•unscheduled GP visits
•oral corticosteroid (OCS) use (maintenance and courses)
•quality of life (Asthma Quality of Life Questionnaire [AQLQ]) and the
Asthma Control Test (ACT).

•These were evaluated for 2 years before treatment and at 16 weeks after
treatment.


•Data were compared for the 2 years prior to commencing omalizumab
and at the most recent assessment following omalizumab therapy.
                         METHODS
14 patients (mean age 40 years [range 19–58]) who had been receiving
omalizumab for an average of 10.5 months (range 3–42 months) were
included in the study.

Patients had a mean duration of asthma history of 17.5 years
(standard deviation [SD] 11.12) and mean IgE serum levels of 654 (SD
912.7) IU/mL.

In the 2 years prior to commencing treatment with omalizumab,
patients had a mean of 2.0 A&E visits, 5.7 hospital admissions and
18.3 GP visits, and had received 6.3 courses of OCS.


All patients were classified as responders to omalizumab (for ≥ 16
weeks) following a physician’s evaluation of treatment effectiveness.
                         RESULTS
Effect of omalizumab on health-care resource and medication
use
•Compared with the 2-year period pre-omalizumab, the total
number of GP visits reduced from 256 to 42, A&E visits from 26
to 7 and hospital admissions from 80 to 9 respectively in the
10.5 months following the introduction of omalizumab, although
the different observation periods should be considered.


•When results were expressed as mean rate per patient per year,
the rate of GP visits and hospitalisations were reduced from 9.15
to 4.40 and 2.85 to 0.86 respectively. There was no change in the
rate of A&E visits, which were very low both pre- and post-
omalizumab.
•Only 2 out of 14 patients had experienced no hospitalisations
prior to the omalizumab introduction, compared with 9 out of 14
patients post-introduction.

•Similarly the number of patients with no A&E visits increased
from 5 to 8, while the number of patients with no GP visits
increased from 1 to 7.

•The mean maintenance dose of OCS was reduced from 6.8 mg to
3.7 mg/day (prednisolone equivalent) and mean number of
courses per year reduced from 3.15 to 2.46.
Figure 1. Mean annual number of GP visits, A&E visits and
hospital admissions, pre- and post-omalizumab (n=14)
Figure 2: Mean (2a) maintenance dose of OCS and (2b) number
    of OCS courses per year, pre- and post-omalizumab (n=14)
Figure 3: Mean (3a) AQLQ and (3b) ACT scores pre-omalizumab
(24 months) and post-omalizumab (mean 10.5 months) (n=14)
Conclusions

•In patients with severe persistent allergic (IgE) mediated asthma,
omalizumab reduced the number of GP visits and hospital
admissions and reduced the requirement for oral corticosteroids,
while improving patient-reported asthma control and quality of life.


•Results from this small group of patients confirm those of previous
large clinical trials, and demonstrate the real-life effectiveness of
omalizumab in a hospital-based setting.
    Respiratory Research in Bradford
   CQAB149B2350 Completed
   CQAB149B2348 Ongoing
   CQVA149A2304 Ongoing
   CQVA149A2303 Just started.
   GSK ZEPHYR COPD study: Accepted as
    a study centre. Aim to start February 2011.

				
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