Post on 06-Feb-2018
Leonardo M. Fabbri Clinica di Malattie dell’Apparato Respiratorio Università degli Studi di Modena e Reggio Emilia Azienda Ospedaliero-Universitaria - Policlinico di Modena
Nuovi trattamenti per la COPD
World COPD Day Roma, Hotel Una
16 Novembre 2011
Leonardo M. Fabbri Clinica di Malattie dell’Apparato Respiratorio Università degli Studi di Modena e Reggio Emilia Azienda Ospedaliero-Universitaria - Policlinico di Modena
Exacerbations in COPD
Current and future treatment
Futuristic treatments
Treatment of co-morbidities of COPD
NUOVI TRATTAMENTI PER LA COPD
Leonardo M. Fabbri
COPD EXACERBATION GOLD 2011
An exacerbation of COPD is an acute event characterized by a
worsening of the patient’s respiratory symptoms that is beyond
normal day-to-day variations and leads to a change in medication
20%-24% (1 year)
2.5%-10% (5 days)
22%-32% (14 days)
13%-33% (14 days)
Hospital mortality
Hospital mortality
Relapse (repeat ER visit)
Treatment failure rate
OUTCOME OF COPD EXACERBATIONS
Seneff et al. JAMA. 1995; 274:1852-1857; Murata et al. Ann Emerg Med. 1991;20:125-129; Adams et al. Chest. 2000; 117:1345-1352; Patil et al. Arch Int Med. 2003; 163:1180-1186.
In hospitalized patients
In ER patients
In ICU patients
In outpatients
LUNG FUNCTION IMPAIRMENT, COPD HOSPITALISATIONS AND
SUBSEQUENT MORTALITY
Garcia-Aymeric et al, Thorax 2011;66:585e590.
COPD severity was associated with a higher rate of severe exacerbations
requiring hospitalisation, although severe exacerbations at any stage were associated
with a higher risk of short-term and long-term all-cause mortality
COPD
Chronic disease
Tashkin D. N Engl J Med 2010; 363: 1184
Hurst et al, N Engl J Med 2010; 363: 1128-38
progressive nature
• lung function
• symptoms
• comorbidities
Exacerbations • typically 1 - 3 per year • frequency proportional to COPD severity • the frequent exacerbator • chronic decline resulting in poorer prognosis ↓ HRQL ↑ hospitalizations ↑ mortality
COPD exacerbations
PNEUMONIA
THROMBOEMBOLISM
ACUTE HEART FAILURE
METABOLIC ACIDOSIS
ANEMIA
CAUSES OF EXACERBATION OF
RESPIRATORY SYMPTOMS IN CHRONIC PATIENTS
BIOCHEMICAL MARKERS OF CARDIAC DYSFUNCTION PREDICT MORTALITY IN
ACUTE EXACERBATIONS OF COPD
Elevated levels of NT-proBNP and troponin T are strong predictors of early mortality among patients admitted to
hospital with acute exacerbations of COPD independently of other known prognostic indicators
The pathophysiological basis for this is unknown, but
indicates that cardiac involvement in exacerbations of COPD may be an important determinant of prognosis
Chang CL et al, Thorax, available on line 9 june 2011
TARGETING THE LUNG ATTACKS
Current management strategies for acute asthma and ECOPD within and subsequent to
discharge from hospital are suboptimal
We suggest that the term ‘lung attack’ may resonate more with patients and the broader
community
FitzGerald JM, Thorax, available on line 9 june 2011
Breast Cancer Diseases - 2015
All Breast Cancers
ER+ 65-75%
HER2+ 15-20%
Triple negative
15%
HER3+
IGFR1+
p95+ 4%
P53mut 30-40 %
FGFR1 Ampl 8%
PTENloss 30-50%
PI3Kmut 10%
BRCAMut 8%
TARGETED THERAPIES IN A-NSCLC Positive Phase III Studies
Monotherapy
ComboTherapy
Erlotinib BR.21
Bevacizumab ECOG 4599/AVAiL
Gefitinib IPASS/INTEREST/NEJG002
EGFR Mut+
1st Line
A-NSCLC
Cetuximab FLEX
2nd /3rd
Line
2005 2008 2009 2007
EGFR Mut+ All
lines
NUOVI TRATTAMENTI PER LA COPD
Leonardo M. Fabbri
Exacerbations in COPD
Current and future treatment
Futuristic treatments
Treatment of co-morbidities of COPD
NUOVI TRATTAMENTI PER LA COPD
Leonardo M. Fabbri
Add ICS OR/AND ROFLUMILAST in “exacerbators”
IV: Very Severe III: Severe II: Moderate I: Mild
Therapy at Each Stage of COPD
• FEV1/FVC < 70% • FEV1 > 80% predicted
• FEV1/FVC < 70% • 50% < FEV1 < 80% predicted
• FEV1/FVC < 70% • 30% < FEV1 <
50% predicted
• FEV1/FVC < 70% • FEV1 < 30%
predicted or FEV1 < 50%
predicted plus chronic respiratory failure
Add one or more long-acting bronchodilators (when needed); Add rehabilitation
Active reduction of risk factor(s); influenza vaccination Add short-acting bronchodilator (when needed)
Add long term oxygen if chronic respiratory failure. Consider surgical treatments
Add ROFLUMILAST
2011 UPDATE OF THE GOLD GUIDELINES
2011 UPDATE OF THE GOLD GUIDELINES
Shanghai, October 2011
First choice Second choice Alternative choice
A SABA or SAMA prn SABA and SAMA LABA or LAMA
Theophylline
B LABA or LAMA LABA and LAMA
Theophylline SABA and/or SAMA
C ICS/LABA or LAMA
LABA and LAMA ICS and LAMA
Theophylline SABA and/or SAMA Consider PDE4-inh*
D ICS/LABA or LAMA
ICS/LABA and LAMA ICS/LABA and PDE4-inh* LAMA and PDE4-inh
Theophylline SABA and/or SAMA Carbocysteine
FIGURE 2. PROPORTION OF PARTICIPANTS FREE FROM ACUTE EXACERBATIONS OF CHRONIC OBSTRUCTIVE
PULMONARY DISEASE (COPD) FOR 1 YEAR, ACCORDING TO STUDY GROUP
Albert RK Et Al, NEJM ,August 25, 2011 vol. 365 no. 8
CHRONIC AZITHROMYCIN DECREASES THE FREQUENCY OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE EXACERBATIONS
Alpert RK et al, New Engl J Med 2011; 365: 689-698
When added to usual treatment, azithromycin, 250 mg taken daily for
one year decreases COPD exacerbations and improves quality of
life but also causes hearing decrements in a small fraction of subjects
THE EFFECT OF TELITHROMYCIN IN ACUTE EXACERBATIONS OF ASTHMA
Johnston SL et al, NEJM 2006;354(15):1589-600
This study provides evidence of the benefit of telithromycin in
patients with acute exacerbations of asthma; the mechanisms of
benefit remain unclear
Corbetta L et al, 2011
TC DEL POLMONE DI PAZIENTE CON ENFISEMA PREVALENTE AI LOBI INFERIORI
Lobi inferiori
Corbetta L et al, 2011
TC DEL POLMONE DI PAZIENTE CON ENFISEMA PREVALENTE AI LOBI SUPERIORI
Lobi superiori
Corbetta L et al, 2011
VALVOLE UNIDIREZIONALI ZEPHYR A BECCO D'ANATRA: PORZIONE ENDOBRONCHIALE CHE ADERISCE ALLA
PARETE BRONCHIALE
Corbetta L et al, 2011
VALVOLA SPIRATION AD OMBRELLINO
Sciurba et al, N Engl J Med 2010; 363;13
A RANDOMIZED STUDY OF ENDOBRONCHIAL
VALVES FOR ADVANCED EMPHYSEMA Endobronchial-valve treatment for advanced heterogeneous emphysema induced modest
improvements in lung function, exercise tolerance, and symptoms
at the cost of
more frequent exacerbations, pneumonia, and
hemoptysis after implantation
Majid A et al, Chest 2008; 134:801–807
TRACHEOBRONCHOPLASTY FOR SEVERE TRACHEOBRONCHOMALACIA*
A PROSPECTIVE OUTCOME ANALYSIS
In experienced hands, surgical central airway stabilization with posterior tracheobronchial splinting using a
polypropylene mesh improves respiratory symptoms, health-related quality of life, and functional status in highly selected patients with severe symptomatic TBM.
Majid A et al, Chest 2008; 134:801–807
DYNAMIC AIRWAY CT
Majid A et al, Chest 2008; 134:801–807
SILICONE STENT
Majid A et al, Chest 2008; 134:801–807
SKETCH SHOWING THE PLICATION OF THE POSTERIOR MEMBRANOUS WALL OF THE TRACHEA AND MAINSTEM
BRONCHUS USING A MARLEX MESH
Majid A et al, Chest 2008; 134:801–807
TRACHEOBRONCHOPLASTY FOR SEVERE TRACHEOBRONCHOMALACIA*
A PROSPECTIVE OUTCOME ANALYSIS
In experienced hands, surgical central airway stabilization with posterior tracheobronchial splinting using a
polypropylene mesh improves respiratory symptoms, health-related quality of life, and functional status in highly selected patients with severe symptomatic TBM.
TIOTROPIUM IMPROVES LUNG FUNCTION IN PATIENTS WITH SEVERE ASTHMA:
a randomised controlled trial
The addition of once-daily tiotropium to asthma treatment including high dose ICS plus LABA,
provides significant improvements in lung-function over 24 hours in patients with
inadequately controlled, severe, persistent asthma
Long-term studies are needed to assess patient
reported outcomes and exacerbation rates.
Kerstjens HAM et al, JACI, August 2011
Castro M et al. Am J Respir Crit Care Med 2010;181:116–24.
This study demonstrates that BT provides clinically meaningful improvements in severe exacerbations requiring corticosteroids, ED visits, and time lost from work/school during the post-treatment period in patients with severe
and inadequately controlled asthma, together with improvements in quality of life.
We conclude that the increased risk of adverse events in
the short-term after BT is outweighed by the benefit of BT that persists for at least 1 year. BT offers clinicians a novel, procedure-based, add-on therapy beyond the current use of
high-dose ICS and LABA to decrease the morbidity of severe asthma.
EFFECTIVENESS AND SAFETY OF BRONCHIAL THERMOPLASTY IN THE TREATMENT OF
SEVERE ASTHMA
Momen M. Wahidi, MD, MBA and Monica Kraft, MD, AJRCCM, in press.
No < airway hyperresponsiveness or > FEV1 > quality of life
< severe exacerbations < emergency department visits < days lost from school or work
bronchospasm
occasionally hospitalization
BRONCHIAL THERMOPLASTY FOR SEVERE ASTHMA
Exacerbations in COPD
Current and future treatment
Futuristic treatments
Treatment of co-morbidities of COPD
NUOVI TRATTAMENTI PER LA COPD
Leonardo M. Fabbri
EMERGING PHARMACOTHERAPIES FOR COPD
Barnes PJ. Chest 2008; 134:1278-1286
Barnes JACI 2007
Expression of CXCR2 on Neutrophils
Pharmacol Rev 56:515-548, 2004
Goblet Cell (discharging)
Ciliated Epithelial
Cells Alveolus
Type I Type II
Smooth Muscle
Neutrophil
Blood Vessel
Capillary
collagen
CXCR2
Macrophage
Eosinophil T-cell
Mast Cell
Contraction Migration
Goblet cell hyperplasia Mucus secretion
Chemotaxis
Microvascular leakage VCAM-1 expression
Fibroblast myofibroblast
Angiogenesis
Airway Epithelium
Blood Vessel
CXCR2 Biology
fibroblast neutrophil
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
Sput
um n
eutr
ophi
ls
Cel
ls X
106
/mL
P = 0.001
P < 0.001
P < 0.001
Screening
Pre ozone Post ozone Placebo SCH 527123 Prednisolone
Effect of 50 mg of SCH527123 on Ozone-Induced Airway Neutrophilia in Healthy Subjects
Holz et al Eur Respir J. 2010: 564-70
TESRA (Treatment of Emphysema with a Selective Retinoid Agonist)
study results
Paul Jones on behalf of TESRA Steering Committee Members and
Investigators
Study design Screening
Period
Up to 6 weeks Start optimized COPD therapy *
N = 492
Safety Follow-Up
Period
4 Weeks
2-year Double-blind Treatment Period
N = 160 Placebo p.o. + optimized COPD therapy
N = 329 Palovarotene (5 mg qd) p.o + optimized COPD therapy
* Optimized COPD therapy = SABA prn + Tiotropium + ICS+LABA (either Advair® or Symbicort® at highest registered dose)
Outcomes (measured every 6 months)
• Post-bronchodilator FEV1 (primary outcome)
• Diffusing capacity
• CT densitometry (15% percentile) measured yearly
• 6-MWD
• SGRQ
• TDI
TESRA Patient Disposition
492 randomized patients
490 patients
2 patients not treated (0.4%)
Placebo 159 patients
Palovarotene 5 mg 329 patients
29 % withdrawals • 15 % due to safety • 14 % non-safety
Dose reduction 3 (2 %) permanent
dose reduction
Dose reduction 28 (9%) permanent
dose reduction
32 % withdrawals • 22 % due to safety • 10 % non-safety
Placebo 114 patients (71 %)
Palovarotene 225 patients (68 %)
Safety pop
Completers
ITT pop Placebo 160 patients Palovarotene 329 patients
1 patient (no efficacy FUP)
1 patient received palovarotene for 28 days
Summary • Palvoratene appears to have low toxicity
• In placebo treated patients, 2 regions of interest in the lower lung (lower half and lowest quartile) showed faster disease progression across most measures
• ITT analysis in whole lung
– Palvarotene efficacy did not differ from placebo
• Post hoc analysis in the lower lung – Palvarotene was associated with less worsening over time in most
outcomes
• These observations require confirmation using more detailed analysis of emphysema progression in different parts of the lung
• If confirmed, the observations from this hypothesis-generating study require testing in patients with lower lung emphysema
Incidence of COPD exacerbations (% of patients)
% of COPD exacerbations leading to:
COPD Exacerbations*
* Defined as worsening of COPD symptoms requiring either orals steroids and/or antibiotics Reported as Adverse Events by Investigator 44
Clustering by expression levels of periostin, CLCA1 and serpinB2 in epithelial brushings identifies two groups of
subjects with asthma
Woodruff et al. AJRCCM 2009
LEBRIKIZUMAB TREATMENT IN ADULTS WITH ASTHMA
Jonathan Corren, Robert F. Lemanske, Jr., Nicola A. Hanania, Phillip E. Korenblat, Merdad V. Parsey, Joseph R. Arron, Jeffrey M. Harris, Heleen Scheerens, Lawren C. Wu, Zheng Su, Sofia Mosesova, Mark D. Eisner, Sean P. Bohen, and John G. Matthews.
August 3, 2011
Corren J et al, N Engl J Med 2011
Results: change in FEV1
Conclusions
Lebrikizumab treatment was associated with
improved lung function.
Patients with high pretreatment levels of serum periostin had greater improvement in lung function with lebrikizumab than did patients with low periostin levels.
Corren J et al, N Engl J Med 2011; August 3, 2011
GATA-3 IS THE MASTER TRANSCRIPTION FACTOR IN TH2-DRIVEN INFLAMMATORY DISEASES
Barnes P, JCI 118 (2008): 3546-3556
THE TRANSCRIPTION FACTORS GATA-3 AND TBET PLAY A CRUCIAL ROLE IN INFLAMMATION
Ansel KM, et al. Annu. Rev. Immunol. 24 (2006): 607-56
SB010: MECHANISM OF ACTION
Miotto D, Boschetto P, Mapp C et al Eur Respir J 2003; 22: 602–608
T-helper-2 and -1 protein expression is present in the central airways of
smokers and interleukin-4 and -13 could contribute to mucus
hypersecretion in chronic bronchitis.
INTERLEUKIN-13 AND -4 EXPRESSION IN THE CENTRAL AIRWAYS OF SMOKERS WITH
CHRONIC BRONCHITIS
Exacerbations in COPD
Current and future treatment
Futuristic treatments
Treatment of co-morbidities of COPD
NUOVI TRATTAMENTI PER LA COPD
Leonardo M. Fabbri
Barnes PJ et al., Eur Respir J 2009;33:1165–1185
SYSTEMIC EFFECTS AND COMORBIDITIES OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE
Clinical Case Report
• Man
• 60 years old
• Occupation trader of fruit
• No familiarity for lung disease
• No occupational/environmental exposures
• Smoker (90 p/y)
Symptoms and signs reported:
♦ fatigue
♦ Chest: reduced murmur
♦ increasing dyspnea (even at rest)
♦ ankle edema
♦ SaO2 (supine, air) 94%; ABP 130/80
Previous clinical history
• COPD (1990) with severe emphysema GOLD III
• Major depression (2000)
• Hypertension (1990)
• Diabetes mellitus type II (2006)
• Chronic pulmonary heart failure(2010)
• Congestive heart failure (2010)
• Obstructive sleep apnea syndrome (2011)
• Obesity (BMI 36)
Home Therapy - Bisoprolol 2,5 mg/day
- Valsaltan 80 mg/day
- Furosemide 250 mg/day
- Canrenoato potassium 100 mg/day
- Venlafaxine 150 mg/day
- Pregabalin 300 mg/day
- Triptych 150 mg/day
- Metformin 1000 mg/day
- Salmeterol/Fluticasone 50/500 1 inhalation/bid
- Tiotropium 18 mcg 1 in./day
- O2 therapy 1 L/min. at night
Diagnostic tests performed
• Blood examination normal [in particolar normal ESR (10 mm), PCR (0.58 mg/dl) and D-dimer (370 ng/ml)] but with mild increase in glycemia (138 mg/dl)
• Arterial blood gas analysis hypoxemia (pH 7.43, pO2 63 mmHg, pCO2 49 mmHg, sO2 92%)
• Respiratory function tests severe obstructive ventilatory failure [FEV1 48% (1.71 L), FVC 71% (3.32 L), TLC 108%, RV/TLC 136%; TLCO(Va) 68%]
• Polysomnography A+H 7,8 / h; mean oxygen saturation 86,8%
• Echocardiogram (August 2011) nothing significant to report, except for a slight increase in PAPs; EF 45%.
Pulmonary emphysema on CT-scan
micronodule of 4 mm
REDUCTION OF MORBIDITY AND MORTALITY BY STATINS, ACE INHIBITORS, AND ARBS IN
PATIENTS WITH COPD
These agents may have dual cardiopulmonary protective properties, thereby substantially altering prognosis of patients with COPD.
These findings need confirmation in
randomized clinical trials.
Mancini JB et al. J Am Coll Cardiol 2006;47(12):2554-60
Β-BLOCKERS MAY REDUCE MORTALITY AND RISK OF EXACERBATIONS IN PATIENTS WITH
CHRONIC OBSTRUCTIVE PULMONARY DISEASE
Rutten FH et al, Arch Intern Med. 2010 May 24;170(10):880-7
Treatment with beta-blockers may reduce the risk of exacerbations and
improve survival in patients with COPD, possibly as a result of dual
cardiopulmonary protective properties
Exacerbations in COPD
Current and future treatment
Futuristic treatments
Treatment of co-morbidities of COPD
NUOVI TRATTAMENTI PER LA COPD
Leonardo M. Fabbri
Leonardo M. Fabbri Clinica di Malattie dell’Apparato Respiratorio Università degli Studi di Modena e Reggio Emilia Azienda Ospedaliero-Universitaria - Policlinico di Modena
World COPD Day Roma, Hotel Una
16 Novembre 2011
Nuovi trattamenti per la COPD
Rossi A, Centanni B, Cerveri I, Gulotta C, Foresi A, Cazzola M, BrusascoV. Respiratory Medicine (2011) xx, 1e7
Diagnosis of moderate (as classified by the Global Initiative for Chronic Obstructive Lung Disease [GOLD] Guidelines, 2007) chronic obstructive pulmonary disease (COPD) and:
Smoking history of at least 10 pack-years
Forced expiratory volume in 1 second (FEV1
< 80% and ≥ 50% of the predicted normal value
Post-bronchodilator FEV1/Forced Vital capacity (FVC) < 0.7
ACUTE EFFECTS OF INDACATEROL ON LUNG HYPERINFLATION IN MODERATE COPD:
A COMPARISON WITH TIOTROPIUM