copd 2014 alejandro c. arroliga, m.d. chairman and professor dr. a. ford wolf and brooksie nell boyd...
TRANSCRIPT
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COPD 2014
Alejandro C. Arroliga, M.D.Chairman and Professor
Dr. A. Ford Wolf and Brooksie Nell Boyd Wolf
Centennial Chair of Medicine
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Organization of the talk
• A.- Inflammation
• B.- Brief review of therapy including for exacerbation (recent papers in red)
• COPD is a systemic disease
2
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PLATINO: COPD in LatinAmerica
Brazil (São Paulo)
Uruguay (Montevideo)
Venezuela (Caracas)
Mexico (Mexico city)
Chile (Santiago)
Menezes A, et al. Lancet 2005
12,1%!!!
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COPD is a progressive disease with inflammation as a key process
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1. Snoeck-Stroband JB et al. Respir Res 2006; 7: 140. 2. Parr DG et al. Respir Research 2006; 7: 136 (online journal).
Understanding inflammation
• Airway inflammation negatively affects health status of COPD patients1
• Higher levels of certain inflammatory markers are associated with a decline in lung function and subsequent disease progression2
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• Airway inflammation is characterised by increased numbers of neutrophils, macrophages and CD8+ lymphocytes1,2
• Infiltration of inflammatory cells into the airways occurs in both early and late stages of COPD3
• As the disease progresses, the small airways fill with inflammatory mucus exudates3
• The presence of inflammation in the airways provides a rationale for using inhaled corticosteroids and long-acting beta2-agonists to treat the disease
1. Gold Guideline http://goldcopd.com 2007. 2. Barnes NC et al. Am J Respir Crit Care Med 2006; 173: 736–743. 3. Hogg JC et al. New Eng J Med 2004; 350: 2645–2653.
Inflammation is present even in the early stages of COPD
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Percentage change from baseline in biopsy and sputum endpoints
1. Barnes NC et al. Am J Respir Crit Care Med 2006; 173: 736–743.
CD8p=0.001
CD68p=0.288
CD45p=0.001
CD4p=0.002
Mast cellsp=0.022
TNF-p=0.007
IFN-p=0.055
Ch
ang
e fa
vou
rsS
FC
Ch
ang
e fa
vou
rsp
lace
bo
30
20
10
0
-10
-20
-30
-40
-50
-60
-70
-80
SF
C 5
0/50
0 –
pla
ceb
o (
%)
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The Anti-inflammatory Effect Is Associated With A Reduced Rate In
The FEV1 Decline
Ann Intern Med. 2009;151:517-527.
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1. Bourbeau J et al. Thorax 2007; 62: 938–943. 2. Kardos P et al. Am J Respir Crit Care Med 2007; 175:144–149. 3. Mahler DA et al. Am J Respir Crit Care Med 2002 166: 1084–1091; 4. Calverley PMA et al. Lancet 2003; 361: 449–456. 5. Calverley PMA et al. New Eng J Med 2007; 356: 775–789. 6. Johnson M. Proc Am Thor Soc 2004; 1: 200–206 7. Adcock IM. J Allergy Clin Immunol 2002; 110(6 Suppl): s261–s268.
Synergistic effects of SFC
• Bourbeau et al suggest that combination therapy has anti-inflammatory effects, not seen with inhaled corticosteroids alone1
• Compared with monotherapy, enhanced effects for combination are consistent not only with clinical data but also with in vitro data2–5
• Bourbeau et al propose that the anti-inflammatory activity seen with SFC but not FP may be due to additive or synergistic effects at the receptor level1
• Corticosteroids may regulate 2 receptor function by increasing expression of the receptor, and inhibiting 2 receptor down-regulation6,7
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COPD 2013
• “patients who benefit the most from inhaled bronchodilators seem to be those who have respiratory symptoms and airflow obstruction with an FEV1 less than 60% predicted”
• “monotherapy using either long acting inhaled anticholinergics or long acting beta agonists(but not inhaled steroids as monotherapy) for symptomatic patients with an FEV1 of less than 60% predicted is recommended
Courtesy of Frank Perez-Guerra, M.D.
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Summary of data of different therapeutic studied in patients with COPD
• UPLIFT (Tiotropium achieves improvement in lung function over time, although rate of decline not reduced; reduction in frequency of exacerbations and in hospitalizations; no difference in mortality between tiotropium and placebo
• TORCH- reduction in the rate of decline in airflow limitation in the salmeterol/fluticasone arm compared to placebo
• INSPIRE – comparison of SFC versus tiotropium in severe COPD – no difference in exacerbation frequency between the two treatments. Question of better quality of life and reduced mortality risk with SFC.
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• Tiotropium/formoterol (Foradil) vs salmeterol(Serevent)/fluticasone in moderate COPD – TF superior in lung function over the day compared to SF (this study appeals to me, Chest 2008;134:255)
• OPTIMAL (Tiotopium/placebo, T plus salmeterol, T plus salmeterol/fluticasone) – patients treated with T/F/S had significantly better disease specific quality of life and fewer hospitalizations compared to T/placebo, however these improvements in health outcomes were associated with increased costs. Monotherapy with T most economically attractive. Exacerbation rate did not differ
Summary of data of different therapeutic studied in patients with COPD
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Others therapy
• Immunizations – both Pneumovax and influenza (this is an “accepted” recommendation)
• Testing for alpha-one-anti-trypsin deficiency –
• Lung volume reduction surgery (or “medical treatment utilizing valves”) - not a common procedure, but may be considered in very symptomatic patients with well documented predominant upper lobe emphysema with an FEV1 and DlCO of more than 20% of predicted
• Transplantation - LVRS may be a bridge to this. When to refer – BODE index of over 5, post dilator FEV1 of less than 20% predicted, resting hypoxemia, hypercapnia, secondary PH, accelerated decline in FEV1 – but…is there a survival benefit?
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Global Strategy for Diagnosis, Management and Prevention of COPD
Manage Stable COPD: Non-pharmacologic
PatientGroup
Essential Recommended Depending on local guidelines
ASmoking cessation (can include pharmacologic
treatment)Physical activity
Flu vaccinationPneumococcal
vaccination
B, C, D
Smoking cessation (can include pharmacologic
treatment)Pulmonary rehabilitation
Physical activityFlu vaccinationPneumococcal
vaccination
© 2013 Global Initiative for Chronic Obstructive Lung DiseaseCourtesy of Shirley Jones, M.D.
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COPD 2013
• Roflumilast – this is a PDE-4 inhibitor (PDE-4 inhibition decreases inflammation and promotes airway smooth muscle relaxation)
• Approved for COPD patients with a history of exacerbations – the experience is limited, but this agent may be useful perhaps not only in COPD, but in asthma, bronchiectasis, etc – time will tell
• Mucoactive agents- the jury is out, but some patients may improve, some even think that they are better than the inhaled medications (but this is doubtful)
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GOLD Assessment
Sev
erity
of A
irflo
w
Obs
truc
tion
Worse obstruction
More severe
Exa
cerb
atio
ns
Frequent exacerbations
DSevere ObstructionSevere Symptoms++ Exacerbations
High
High
High
Risk
Risk
Risk
Symptoms
CSevere ObstructionMinimal Symptoms++ Exacerbations
AMild-Mod ObstructionMinimal SymptomsFew Exacerbations
BMild-Mod Obstruction
Severe SymptomsFew Exacerbations
GOLD Website. http://www.goldcopd.com. Updated December 2011
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Survival shown as Kaplan-Meier curves
Lange et al AJRCCM 2012; 186: 975–981
Groups C and D experienced a higher incidence of exacerbations in the following year and a higher average number of exacerbations per year than groups A and B.
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Exa
cerb
atio
ns p
er y
ear
> 2
1
0
mMRC 0-1CAT < 10
RiskFEV1
GOLD 4or
mMRC > 2CAT > 10
GOLD 3
GOLD 2or
GOLD 1
SAMA prnor
SABA prn
LABA or
LAMA
ICS + LABAor
LAMA
COPD: Pharmacologic Therapy(FIRST CHOICE)
A B
DCICS + LABA
or LAMA
• In alphabetical order
Symptoms
Risk
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Exacerbations Are Not Random Events
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Gold Stage AECOPD Rate in Yr 1
II 0.85
III 1.34
IV 2.00
Risks of COPD Exacerbations
Strongest predictor of an AECOPD in a given year was the presence of an exacerbation in the previous year
Hurst JR et al. N Engl J Med 2010; 363:1128-1138
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22Agusti A, et al. Eur Respir J 2013; 42: 636
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PA:A ratio of more than 1 at baseline was associated with future exacerbations of COPD, particularly those requiring hospitalization
23
The PA:A ratio also appears to outperform many established risk factors for exacerbation including GERD, SGRQ score, breathlessness, chronic bronchitis, and FEV1,as well as recently identified CT predictors.
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0.029%SFC vs FP0.00212%SFC vs sal
<0.00125%SFC vs placebo
SFC significantly reduces exacerbations and severity of exacerbations over 3 years (TORCH)
p-valueTreatment effect
0
0.2
0.4
0.6
0.8
1
1.2
Placebo
An
nu
alis
ed e
xace
rbat
ion
rat
e
Sal FP SFC
25% (p<0.001)
1.13
0.97 0.930.85
1. Calverley PMA et al. New Eng J Med 2007; 356: 775–789.
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Treatment of ambulatory exacerbations of mild-moderate COPD is more effective with antibiotic vs. placebo
Primary and Secondary Outcomes
AMX (500/125 mg/8 hrs) %N=158
PBO %N= 152
P value
Clinical cure days 9-11* 74 59 0.016
Clinical cure at day 20 81 67 0.006
Days until exacerbation, median
233 (110-365) 160 (66-365) 0.015
Peak expiratory flow from basal , L/min
52 38 0.039
25
The NNT is seven
Llor C, et al Am J Respir Crit Care Med 2012; 186: 716
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In patients presenting to the ER with acute exacerbation, 5-day treatment of prednisone (40mg daily) was noninferior to 14-day treatment
• Non inferiority was defined as a 15% absolute difference in % of patients with a re-exacerbation (6 months)
• Average FEV1 was 31% and 87% were GOLD 3 or 4
26
End point Conventional treatment (n=155)
Short- term (n= 156)
Comparison measure (95%CI)
P value
Reexacerbations (ITT)
36% 35% HR 0.95 (0.70-1.29) 0.006
Deaths follow up 8% 7% HR 0.93 (0.40-2.20) .87
Need for MV 13% 11% OR 0.78 (0.37-1.63) .49
Cumulative dose, median, mg
560 (560-773) 200 (200-310) <0.001
Leuppi JD, et al. JAMA 2013; 309: 2223-2231
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COPD affects more than the lungs!
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TORCH overall causes of death as adjudicated by the Clinical Endpoint Committee
Unknown7%
Cardiac 27%
Cancer21%
Other10%
Respiratory35%
1. Calverley PMA et al. New Eng J Med 2007; 356: 775–789.
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84% of COPD patients in TORCH study had comorbidities in at least one body system
53
34
2521
18 18 1714 14 12 11 10 10 9
4 4
% to
tal p
opul
ation
n=6112
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Clinical consequences of osteoporosis
• Acute and chronic
pain
• Kyphosis
• Loss of height
• Loss of mobility
• Bulging abdomen, reflux and other GI
symptoms
• Breathing difficulties
• Depression
• Loss of independence
REDUCED QUALITY OF LIFECourtesy of Tony Anzueto, M.D.
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What Do COPD Patients Die From?
Mannino et al. Thorax. 2003;58:388-393.
1000 20 40 60 80
Severe COPDGOLD Stage IIIGOLD Stage III
Moderate COPDGOLD Stage IIGOLD Stage II
No COPDGOLD Stage 0GOLD Stage 0
COPD ASCVD Lung Cancer Pneum/Inf Other
Patients (%)
Courtesy of Tony Anzueto, M.D.
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Prevalence of CVD in COPD
Curkendall et al, AEP 2006
Angina Other Cardiovascular Disease
Pulmonary Embolism
StrokeAcute Myocardial Infarction
Arrhythmia
Odds ratio
Congestive Heart Failure
0
1
2
3
4
5
6
7
8
Courtesy of Tony Anzueto, M.D.
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β-blockers can be used in patients with COPD and heart failure
• To explore the interaction of β-blocker selectivity and outcomes the authors queried the OPTIMIZE-HF registry
33Mentz RJ, Am J Cardiol 2013; 111: 582-87
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34
β-blockers can be used in patients with COPD and heart failure
Mentz RJ, Am J Cardiol 2013; 111: 582-87
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35
Mentz RJ, Am J Cardiol 2013; 111: 582-87
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Conclusions
• The burden of COPD is high and is rising1
• COPD is a multicomponent disease with inflammation at its core2
• It is important to treat the underlying inflammation, which is present even in the early stages of the disease3,4
• Patients on SFC have significantly improved lung function and quality of life, and a significant reduction in exacerbations compared with components or placebo5
1. Murray CJL et al. Lancet 1997; 349:1498–1504. 2. Agusti AGN et al. Eur Respir J 2005; 99: 670–682. 3. Hogg JC et al. New Eng J Med 2004; 350: 2645–2653. 4. Barnes NC et al. Am J Respir Crit Care Med 2006; 173: 736–743. 5. Calverley PMA et al. New Eng J Med 2007; 356: 775–789.
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Conclusions
• Exacerbations are common. Patients with previous exacerbations are more likely to have more. Presence of cough and sputum production are associated with more exacerbations
• Antibiotics are useful to treat exacerbations in patients with mild to moderate COPD
• Prednisone 40 mg daily for 5 days is enough
• Use of β-blockers in patients with HF, even non selective are well tolerated and may be associated with improve survival
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38
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COPD : a vision for the next 10 years
Understanding airway obstruction
Improved drug delivery
New LABAs and LAMAs
Combinations LAMA + LABA
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Ultra long-acting β2 agonists under development
Vilanterol
Olodaterol
Abediterol (LAS-100977)
AZD3199
PF-610355 (?)
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NEW LABAs
Cazzola M, et al. Respir Med 2013
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Disease Severity: BDs +/- ICS
Decramer M, et al. Respir Med 2013
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New LABA’s
van Noord JA, et al. Pulm Pharmacol Ther 2011
n=35FEV1: 37 ± 9%TBD: 21 ± 8%Respimat
n=35FEV1: 37 ± 9%TBD: 21 ± 8%Respimat
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Long-acting antimuscarinic agents
Glycopyrronium (NVA-237)Umeclidinium (GSK-573719)
Aclidinium
TD-4208 CHF 5407QAT370
BEA-2180BR Trospium
DexpirroniumAZD8683
PF-3715455 or PF-3635659
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New LABA - NAV 237
Kerwin E, et al; GLOW2. Eur Respir J 2012
n=1066FEV1: 55,7 ± 13%TBD: 16 ± 15%Breezhaler
n=1066FEV1: 55,7 ± 13%TBD: 16 ± 15%Breezhaler
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New LAMA’s
Jones PW, et al; ATTAIN. Eur Respir J 2012
n=828FEV1: 53 ± 14%TBD: –Genuair
n=828FEV1: 53 ± 14%TBD: –Genuair
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COPD : a vision for the next 10 years
Understanding airway obstruction
Improved drug delivery
New LABAs and LAMAs
Combinations LAMA + LABA
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The present and future
LAMAs
• Tiotropium
• Glycopyrronium (NVA237)
• Umeclidinium bromide
• Aclidinium bromide
LABAs
• Oledanterol
• Indacaterol
• Vilanterol
• Carmoterol
• Formoterol
• Salmeterol
Fixed - Combinations- Olodaterol/ tiotropium-Umeclidinium/ vilanterol -- Indacaterol/ glycopyrronium - Formoterol/aclidinium-Formoterol/glycopyrrolate
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Rationale for combining long-acting bronchodilators
• Inhaled bronchodilators are the foundation of COPD treatment
• Most patients with COPD improve with bronchodilation
• Maximal bronchodilation is not achieved using clinically approved doses of 1 class of bronchodilator alone
• There could be synergistic interactions between 2-agonists and anticholinergics
Cazzola M, Molimard M. Pulm Pharmacol Ther 2010;23:257-67
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Ipratropium + Albuterol
Combination short acting therapy
40
50
60
70
80
90
100
0 15 30 45 60 75 90 105 120
% R
esp
ond
ing
Albuterol Ipratropium
Minutes post-drug administration
Dorinsky PM, et al. Chest. 1999;115:966–971.
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Combining tiotropium and formoterol (dosed once or twice daily): FEV1
1.5
1.4
1.3
1.2
1.1
0.9
1.0
0 2 4 6 8 10 12 14 16 18 20 22 249 AM 3 PM 9 PM 3 AM 9 AM
FEV
1 (
L)
van Noord JA et al. Chest 2006;129:509-17
Time (hours)
Tiotropium qd + formoterol bidTiotropium qd + formoterol qd
Tiotropium qd + placebo bid24-hour base
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Effects of tiotropium and formoterol on dynamic hyperinflation and exercise endurance in COPDtime to exercise intolerance FEV1
Berton et al. Respiratory Medicine 2010; 104: 1288-96
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Combination: LABA + LAMA
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Nuevas evidencias en LABA-LAMA2
Bateman E, et al; SHINE. ERS Congress 2012
5m 1h 2h 4h 8h 16h 22h 24\912h
Time
1.601.551.551.451.401.351.301.251.201.151.101.051.00
LS
me
an
of
FE
V1(
L)
QVA149 Indacaterol Glycopyrronium Open-label tiotropium Placebo
54/46
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LABA + LAMA vs ICS/LABA
Vogelmeier CF, et al; ILLUMINATE. Lancet 2012
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Four weeks once daily treatment with tiotropium + olodaterol fixed dose combination compared with tiotropium in COPD patients
0
50
100
150
200
250
300
350
400
450
T 5μg T+O 5/2μg T+O 5/5μg T+O 5/10μg
Peak FEV1 response (mL)
Trough FEV1 response (mL)
* *
*
*
Maltais et al, ERS Congress 2010
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FEV1 after 4 weeks of treatment
aMean values adjusted for baseline, treatment and centre
1.20
1.30
1.40
1.50
1.60
-1 0 1 2 3 4 5 6Time (hours)
FE
V1
(L)a
T+O (5 / 10 µg)T+O (5 / 5 µg)
T+O (5 / 2 µg)
T (5 µg)
Maltais F et al. P5557 presented at ERS 2010
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28-day safety and tolerability of umeclidinium incombination with vilanterol in COPDChange from baseline in 0–6 h weighted mean pulse rate
Feldman et al, Pulm Pharmacol Ther 2012
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(Ultra) LABA/ICS combinations in clinical development
Formoterol + mometasone (MFF258)Formoterol + fluticasone propionate
Formoterol + ciclesonideIndacaterol + mometasone (QMF-149)
Indacaterol + QAE-397Vilanterol + fluticasone furoate
GS-424020 (novel mutual prodrug of salmeterol and desisobutrylciclesonide)
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Cazzola et al, Expert Opin Pharmacother 2012
Triple combination therapies in Phase I and II clinical trials
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COPD: Drug Combinations (in alphabetical
order)
Patient
First choice Second choiceAlternative
Choices
ASAMA prn
or SABA prn
LAMA or
LABA or
SABA and SAMA
Theophylline
BLAMA
or LABA
LAMA and LABASABA and/or
SAMATheophylline
C
ICS + LABAor
LAMALAMA and LABA
PDE4-inh.SABA and/or
SAMATheophylline
D
ICS + LABAor
LAMA
ICS and LAMA orICS + LABA and LAMA
or ICS+LABA and PDE4-
inh. orLAMA and LABA or
LAMA and PDE4-inh.
CarbocysteineSABA and/or
SAMATheophylline
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MABA: LABAS + LAMALABA
Long-acting beta agonistLABA
Long-acting beta agonistLAMA
Long-acting muscarinic antagonistLAMA
Long-acting muscarinic antagonist
MABAMuscarinic antagonist and beta agonist
Hughes AD, et al. Prog Med Chem 2012
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Astra Zeneca – PATHOS Study• Objectives:– To investigate exacerbation rates in primary care patients with COPD treated with BF vs FS.• Methods:– Data from primary care medical records.– Pairwise (1:1) propensity score matching.• Results– Matching of 9893 patients (7155 BF; 2738 FS yielded two cohorts of 2734 patients), comprising 19,170 patient-years.– The exacerbation rates were 0.80 and 1.09 per patient-year BF and FS – Yearly rates for COPD-related hospitalizations were 0.15 and 0.21, respectively• Conclusions– Long-term treatment with fixed-combination BF was associated with fewer exacerbations than FS in patients with moderate and severe COPD.
Journal of Internal Medicine 2013 in press.
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New ICS-LABAS combination
Martinez F et al Respiratory Medicine 2013; 107: 550
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Inhibition of release ofinflammatory mediators by p38 inhibitors
- Signalling through p38 mitogen-activated protein kinase (p38-MAPK) is required for the expression of a range of inflammatory mediators associated with COPD such as tumor necrosis factor α, interleukin-1 (IL-1), IL-6 and IL-8.- PH-797804 is a potent, selective p38-MAPK
MacNee W, et al. Thorax 2013
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Novel classes of bronchodilators
• Selective phosphodiesterase inhibitors
• K+ channel openers
• Vasoactive intestinal peptide analogs
• Rho kinase inhibitors
• Brain natriuretic peptide and analogs
• Nitrix oxide donors
• E-prostanoid receptor 4 agonists
• Bitter taste receptor agonists
Cazzola et al, Pharmacol Rev 2012
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COPD : a vision for the next 10 years
• Further understanding of the impact of long acting bronchodilators.
• Demonstrate the efficacy of intervention in milder disease.
• New delivery systems
• Provide maximum bronchodilation - combination therapy – LABA-LAMA
• New molecules