Advances in COPD Management and Smoking Cessation by osx43699


									Advances in COPD Management
    and Smoking Cessation

           September 12th, 2009

     Mark S. Regan, M.D.
     Section of Allergy, Pulmonary, and Critical Care

Part   1 – Acute Exacerbations of COPD

Part   2 – Pharmacologic Management of stable COPD
            –Safety of Medications
            –Smoking Cessation
Part I – Acute Exacerbations of COPD
   Definition,   Epidemiology, Risk Factors
   Etiologies
   Management
     – Antibiotics
     – Corticosteroids
     – Oxygen
     – Non-invasive ventilatory support
AE-COPD: ‘Event-Driven’ Definition

        “An event in the natural course of the
     disease characterized by a change in the
     patient’s baseline dyspnea, cough, and/or
     sputum that is beyond normal day-to-day
    variations, is acute in onset, and may warrant
      a change in the regular medication in a
            patient with underlying COPD”

               GOLD Am J Resp Crit Care Med 2007 176:532
AE-COPD: Implications
    Typically occur 1 to 3 times per year
    50% not reported to physician
    3 to 16% will require hospitalization
    Hospital mortality 3 to 10%
    Need for ICU increases mortality to 15 to 30%
    ~14% of patients hospitalized will die within three
    months of admission
    Adverse effects on functional status and QOL,
    with typically slow recovery
    May contribute to accelerated loss of lung
Risk Factors for Frequent (>3/y) AE-COPD
     Advanced    age
     Severity of FEV1 impairment
     Chronic sputum production
     Frequent past exacerbations
     Hospitalization within the last year
     Co-morbidities
      – IHD
      – CHF
      – DM
AE-COPD: Symptoms
   Increased   dyspnea
   Increased cough
   Increased sputum purulence
   Increased sputum volume
   Upper airway symptoms (colds and sore throats)
   Increased wheeze
   Chest tightness
   Reduced exercise tolerance
   Fluid retention
   Acute confusion
AE-COPD: Diagnostic testing
   CXR - patients presenting to ER or hospital
            » 15 to 25% have abnormalities that lead to
              management change based on observational studies
      Spirometry not recommended
            » Not useful in judging severity or guiding management
      ABG
            » Accurate assessment of arterial oxygenation
            » Assessment of hypercapnea; need for vent support
     Sputum samples of limited value
            » Empiric therapy is effective
            » Prompt initiation of antibiotic if sputum purulent
            » Obtain in those requiring hospitalization
     BNP

                           Thorax 2004; 59(Supp I). Snow V. Chest 2001; 119:1185
AE-COPD: Etiology
   Infectious,   80%
    – Bacterial pathogens, 25%-30%
    – Viruses, 25%-30%
    – Viral-Bacterial co-infection, 25%-30%
    – Atypical bacteria, 5%–10%
   Noninfectious,   20%
    – Environmental factors (NO2, SO2, Ozone,
      particulates, etc.)
    – Noncompliance with medical therapy
    – Unidentifiable

                                 Sethi S. Chest. 2000;117(suppl):380S
Viral AE-COPD: Clinical Presentation

      AE-COPD manifestations
        – Increased dyspnea, 76%
        – Increased sputum volume, 62%
        – Increased sputum purulence, 39%
      Anthonisen type
        – Type 1 (all 3 of above symptoms), 20%
        – Type 2 (2 of above symptoms), 46%
        – Type 3 (1 of above symptoms), 34%
      64% of AE-COPD associated with prior cold (18 days)

                     Seemungal T et al. Am J Respir Crit Care Med. 2001;164:1618
AE-COPD: Viral Detection and Symptoms

  39.2%   of AE-COPD
   associated with viral                                     25

                               % of reported exacerbations
  URI, increased                                            20

   dyspnea with URI,
   and sore throat                                           15
   associated with viral
   isolation                                                 10


                                                                  RV   Corona Infl A   Infl B Parainfl Adeno RSV

                  Seemungal T et al. Am J Respir Crit Care Med. 2001;164:1618
AE-COPD: Severity of COPD and Pathogen

Mild-Moderate COPD
     FEV1 > 50%
     No risk factors for poor outcome
     No recent antibiotic therapy                       H. influenza
                                                                 S. pneumoniae
                                                                        P. aeruginosa

                                                                        M. catarrhalis


 1.    Sethi S. Infect Dis Clin N Am 2004; 18: 861-882
 2.    Fabbri. Eur Respir J 2003; 22:1-2
 3.    Miravitlles, et al. Chest. 1999; 116:40-46
AE-COPD: Severity of COPD and Pathogen

Severe to Very Severe COPD, with risk factors for poor outcome
        FEV1 < 50%
        Comorbid cardiac disease
        3 or more exacerbations in 12 months
        Antibiotic therapy within 3 months
                                                             H. influenza

                                                                   S. pneumoniae

                                                                     P. aeruginosa

                                                            M. catarrhalis
    1.    Sethi S. Infect Dis Clin N Am 2004; 18: 861-882
    2.    Fabbri. Eur Respir J 2003; 22:1-2
    3.    Miravitlles, et al. Chest. 1999; 116:40-46
   Treatment Options for AE-COPD
 Removal of irritants                   Corticosteroid therapy
  •dust, pollutants,                       •oral, IV, or inhaled
   cigarette smoke

  •-agonists,                                 Antibiotics
                         Low-flow oxygen
                        Ventilatory support
AE-COPD: Review of Steroid Trials
     Medline & Cochrane database review
     Relevant English language RCT’s - steroid vs placebo
     Trials assessed for:
        – Quality
        – Clinically relevant end points such as relapse, LOS
        – FEV1
     Among 8 studies:
        – 5 found improvement in FEV1 with steroids
        – 2 found improvement in clinical outcomes
        – 1 published and 2 abstracts failed to demonstrate FEV1

                                    Singh, J. Arch Intern Med 2002;162:2527
Oral Prednisone after ER Rx of COPD
     RCTof prednisone vs placebo for
     outpatient exacerbations
      – 147 patients initially evaluated in ED
      – Treatment with 40 mg prednisone for 10 days
      – Antibiotics and inhaled bronchodilators
      – Primary endpoint was relapse
          » return visit for dyspnea within 30d

                            Aaron, S. et al, NEJM 2003; 348:2618
Prednisone Reduces Risk of Exacerbation Relapse



   Kaplan-Meier Estimates of the Probability of Remaining Relapse-free at 30 days

                                                Aaron, S. et al, NEJM 2003; 348:2618
AECOPD – Steroids in outpatients
     Shorten recovery time, improve lung function (FEV1)
      and hypoxemia (PaO2) – supported by multiple small
     May reduce the risk of early relapse and treatment
     Targets – outpatients with dyspnea as most prominent
      symptom, and a baseline FEV1 < 50% predicted
     Dose - 30 to 40mg prednisone/day
     Duration of therapy - 7-10 days recommended
     Consider health consequences of frequent short
      courses (osteoporosis)
     Role of inhaled steroids in acute disease not defined

                           GOLD Am J Resp Crit Care Med 2007 176:532
AECOPD – Steroids in hospitalized patients

       improve lung function (FEV1) and symptoms,
        shorten hospital stay, decrease treatment failure
        rate – supported by multiple RCT’s
       May decrease recurrence rate out to 3 months
       Targets – all hospitalized patients
       Dose - 30 to 40mg prednisone/day
       Duration of therapy - 7-10 days recommended
       Role of inhaled steroids in acute disease not

                            GOLD Am J Resp Crit Care Med 2007 176:532
AE-COPD: Controlled Oxygen Therapy

 Oxygen   therapy is “the cornerstone of hospital treatment”
 Excess O2 should be avoided (hyperoxia induces
 O2 should not be withheld for fear of hypercapnea
 Titrate O2 to maintain PaO2 at approx 60 mmHg or sat 90-
 Repeat ABG after 30 to 60 min
 After discharge reassess need for O2 initiated during AE-
    – 50% will no longer meet criteria for home O2 one
      month following discharge

                    GOLD Am J Resp Crit Care Med 2007 176:532
    AE-COPD: Non Invasive Ventilation
   Decreases the need for intubation/ventilation
   Decreases morbidity/mortality
   Decreases length of ICU and hospital stay
   Selection criteria:
    – Severe dyspnea with acc. muscle use and abdominal paradox
    – persistent acidosis despite adequate bronchodilators (ph<7.3)
    – Respiratory frequency >25 breaths/min
   Requires awake/alert/cooperative/hemodynamically
         stable pt
   If no improvement in 4 hours, unlikely to benefit

                         GOLD Am J Resp Crit Care Med 2007 176:532
Benefit of NIPPV for AE-COPD: Meta-analysis of 11 Studies

             28% Reduction in Intubation

                            Keenan, S. P. Ann Intern Med 2003;138:861
Benefit of NIPPV for AE-COPD: Meta-analysis of 11 Studies

        10% Reduction in In-Hospital Mortality

                            Keenan, S. P. Ann Intern Med 2003;138:861
AE-COPD: Antibiotics
   Approx     50% to 80% exacerbations due to
    infectious etiology
   It’s likely that nearly 50% are related to
    bacterial infection
   Especially helpful in severe exacerbations
   Those with purulent sputum appear to be
    more likely to benefit
   Antibiotic resistance due to over-
    AE-COPD: Color of Sputum

   121 patients with acute exacerbations
   Green vs. white sputum
   94.4% sensitive & 77% specific for bacterial species
     White sputum is unlikely to be bacterial bronchitis
     Green sputum may or may not be bacterial bronchitis

                                 Stockley RA et al, CHEST 2000;117:1638-45
Treatment failures in AE-COPD
 Does choosing the correct antibiotic matter?

         Percent failure






                                          Adams S et al, CHEST
                                          2000; 117:1345-52
COPD Exacerbation- outpatient
      increase  inhaled anticholinergic and 2 agonist
       agents (e.g. 4 puffs q 4h)
      consider prednisone 30-40 mg/d over 7-10 days
      antibiotic if change in sputum color, in conjunction
       with at least one other cardinal symptom
        – Doxycycline, TMP/sulfa, Amoxicillin
        – reserve expensive broad spectrum agents for
            » initial Rx failures
            » frequent exacerbations (>3/yr), recent antibiotic
              therapy, presence of serious co-morbidities
            » advanced disease (FEV1<50%)
COPD Exacerbation- hospitalized
     High   doses of 2 agonist (e.g. albuterol)
       – MDI/spacer 6 to 8 puffs every 1/2 to 4 hours
       – Nebulized
     Ipratroprium
       – MDI/spacer 6 to 8 puffs every 4 hours
       – Nebulized
     Systemic   steroids
       – methylprednisolone IV or prednisone PO – equivalent of 30-40
         mg of prednisone daily for 7-10 days
     Antibiotics
       – Treat patients that require NIV or MV
       – Consider risk factors for infection with P. aeruginosa
       – 5 to 7 day course is sufficient
The Bottom Line…
   AE-COPD     have a deep, often prolonged,
    impact on lung function and quality of life
   Patients with FEV1 < 50% are most severely
   The impact can be blunted by early
    initiation of therapy, and this requires effort
    in educating at-risk patients, with
    consideration for an action plan
   Prevention is key
Part II - Phamacologic
Management of stable COPD

•Recent   important trials

•Safety   of COPD medications

•Smoking    Cessation
Management of Stable Disease

 Airflowobstruction is a constant feature of COPD
  and therefore continuous bronchodilation is a
  reasonable goal

 Therapy  with long-acting beta-agonists or anti-
  cholinergics is now preferred
   – favorable side effect profile
   – more consistent bronchodilation than that
     achieved with Ipratropium QID
   – improved health status and decreased
Lung function decline over 5 years in smokers with
COPD in the Lung Health Study

                  Anthonisen, NR, Connett, JE, Kiley, JP, et al, JAMA 1994; 272:1497

   May have significant anti-inflammatory activity – a small
    study demonstrated decreased parameters of airway
    inflammation vs. ICS…at a mean concentration of 6.32

   It has been proposed that this anti-inflammatory effect may
    be particularly relevant to COPD, which is a relatively steroid-
    resistant disease

   may favorably affect the major factors that reflect functional
    impairment in COPD: dyspnea ratings; exercise capacity;
    respiratory mechanics; and respiratory muscle strength
Inhaled Corticosteroids (ICS)

    Burge et al (ISOLDE trial, BMJ 2000)
      – 751 patients with moderate to severe COPD (mean FEV1 50% of
      – treated with inhaled fluticasone propionate or placebo over a
        3-year period
      – the median annual exacerbation rate was 25% lower in the
        study group (1.32 in the placebo group vs 0.99 in the
        fluticasone group [P = 0.026]).
      – This was a secondary outcome measure

    The Lung Health Study (NEJM, 2000)
       – inhaled steroid (triamcinolone) group had significantly fewer
         visits to a physician due to respiratory illness, suggesting that
         triamcinolone also reduced the frequency of COPD
Inhaled Corticosteroids (ICS)

 Inhaled steroids (ICS) are widely used for COPD
 patients, although scientific basis is not well-
 established for milder disease

 ICSdo not alter the decline in FEV1, but do reduce
 the rate of exacerbations and decline in health
 status in patient with more severe disease

 ICSappear to be associated with fewer
 hospitalizations and lower mortality, but available
 studies have limitations
  Recent   meta-analysis of 9 randomized, controlled
    – All comparing Salmeterol with placebo
    – All at least 12 weeks in duration
    – Total of 3580 patients
    – patients treated with salmeterol over 12 months
      were less likely to suffer a moderate/severe
      exacerbation compared to those receiving
      placebo (34% vs 39%, P<0.0001)

                          Stockley et al, Respir Res. 2006;7:147

   Unique feature is prolonged bronchodilation (>24 hours) due
    to prolonged blockade of M3 muscarinic receptors

   Clinical trials have consistently shown improvements in
    clinically relevant outcomes (symptom scores, quality of life,
    rate of acute exacerbations) relative to placebo

   In long-term trials with FEV1 as primary outcome variable,
    tiotropium was statistically superior to ipratropium QID and
    salmeterol BID

   These trials did not find consistent statistically significant
    differences between tiotropium and salmeterol in terms of
    clinically relevant outcomes
TORCH trial
    Compared salmeterol with fluticasone propionate,
     placebo, and a salmeterol/fluticasone combination in a
     3-year study involving 6112 patients with COPD
    primary outcome measure was death from any cause,
     with exacerbation frequency a secondary outcome
    annual exacerbation rate in the combination therapy
     group was 0.85 (95% confidence interval [CI], 0.80-
     0.90) and 1.13 (95% CI, 1.07-1.20) in the placebo group
     - a reduction of 25%
    Exacerbation rates in the salmeterol and the
     fluticasone groups were significantly lower than in the
     placebo groups

                            Calverley et al. N Engl J Med. 2007;356:775-789
TORCH trial

              Calverley PM. N Engl J Med 2007; 356: 775–89
TORCH trial

   Annual hospital admission rates were 17% lower in the
    combination and salmeterol groups than in the placebo
    group (P≤0.03)

   The probability of having pneumonia was significantly
    greater with fluticasone

   Mortality rates in the fluticasone group were 16.0%,
    compared to 15.2% in the placebo group, 13.5% in the
    salmeterol group, and 12.6% in the combination group

                       Calverley et al. N Engl J Med. 2007;356:775-789
Pooled effect estimate on mortality for all combined
inhalers versus placebo

               Cochrane Database of Systematic Reviews, 17 October 2007 in Issue 4, 2007
INSPIRE trial – Advair vs. tiotropium

   1323 patients with severe COPD randomized to Advair 500/50 BID vs.
    tiotropium 18 mcg daily for two years
   Primary outcome – acute exacerbations of COPD
   Secondary outcomes – mortality, pneumonia, HRQOL

   There was no significant difference in primary outcome variable
   There was a significantly greater probability of study withdrawal with
    tiotropium than with Advair
   SGRQ score was significantly lower at 2 years with Advair vs.
    tiotropium, but this result may not be clinically significant
   Pneumonia was more frequently diagnosed in the Advair group
   Mortality was unexpectedly lower in the Advair group (3% vs. 6%,

                      Wedzicha, et al. Am J Respir Crit Care Med Vol 177. pp 19–26, 2008
UPLIFT trial

   4 year randomized, placebo-controlled, double-blind trial
    comparing tiotropium with placebo in patients with severe
   5993 patients were randomized
   Co-primary outcome variables were FEV1 decline
    (pre/post BD)
   Secondary outcome variables included changes in SGRQ,
    rate of exacerbations, and mortality
   At 4 years, tiotropium did not significantly reduce the rate
    of decline in FEV1
   There was significant impact on secondary outcome
    variables – exacerbation rate, SGRQ

                        From Tashkin, et al. n engl j med 359;15 october 9, 2008
Tiotropium +/- add-on therapy

    Aaron et al randomized 449 patients to 1 of 3 treatment
     groups for a 1-year period: tiotropium plus placebo (n =
     156), tiotropium plus salmeterol (n = 148), and tiotropium
     plus fluticasone/salmeterol (n = 145)
    the proportion of patients who experienced at least 1 COPD
     exacerbation did not differ significantly between the 3
     groups (primary outcome variable)
    more than 40% of patients receiving only long-acting
     Bronchodilators without the steroid component discontinued
     the trial prematurely
    the addition of fluticasone/salmeterol to tiotropium therapy
     did improve clinically important secondary outcomes, such
     as number of hospitalizations for COPD exacerbations,
     disease-specific QOL, and lung function
    There was not a significant difference in rate of SAE’s
     between groups
                         Aaron et al. Ann Intern Med. 2007;146:545-555
Other pharmacologic therapy?

   Biologics – infliximab (TNF alpha inhibitor)

   PDE4 inhibitors

   Macrolide antibiotics

   Retinoids

   Sildenafil, Bosentan

   Statins



 Tiotropium
Meta-analysis of ICS added to LABA

        From Sobieraj, et al. Clinical Therapeutics/Volume 30, Number 8, 2008
Meta-analysis of randomized controlled trials of inhaled
corticosteroid (ICS) use vs control treatment for any pneumonia

                                    From Singh, et al. Arch Intern Med. 2009;169(3):219-229
Meta-analysis of Randomized Controlled Trials of Inhaled Anticholinergics
vs Control for Major Adverse Cardiovascular Outcomes Composite

                                    From Singh, et al. JAMA, September 24, 2008—Vol 300, No. 12
UPLIFT – rate of adverse events
        Incidence Rate of Serious Adverse Events per 100 Patient-Years

                                 From Tashkin, et al. n engl j med 359;15 october 9, 2008
Smoking Cessation
Pharmacotherapies for Tobacco Dependence

            Product                FDA approval   OTC

            Nicotine gum            1984          1996

            Nicotine patch          1991          1996

            Nicotine nasal spray    1996

            Nicotine inhaler        1997

            Nicotine lozenge                      2002

            Bupropion SR            1997

            Varenicline             2006

   partial agonist selective for α4β2 nicotinic acetylcholine receptor

   Two randomized trials, which used the same design and included a
    total of 2052 patients, compared varenicline 1 mg twice daily for 12
    weeks, bupropion 150 mg twice daily for 12 weeks, and placebo

   The primary endpoint of four-week continuous abstinence rate from
    weeks 9 through 12 was higher with varenicline than with bupropion
    or placebo in both trials (44 versus 30 and 18 percent, respectively).

   Post-marketing monitoring has revealed serious neuropsychiatric
    symptoms, including changes in behavior, agitation, depressed
    mood, suicidal ideation, and attempted and completed suicide
Thank you

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