2. ASTMA KAO FAKTOR RIZIKA ZA HOBP
Silva GE, et al. Chest. 2004;126(1):59-65.
0 5 10 15 20
1.0
0.9
0.8
0.7
Inaktivna astma
Bez astme
Aktivna astma
Vreme u godinama
ProcenatpacijenatabezHOBP
HR za razvoj HOBP
aktivna astma vs bez astme
12.5
(95%CI, 6.84 do 22.84)
Prospektivna, observaciona studija
n= 3099
12 upitnika
11 spirometrija
tokom 20 godina
3. HOLANDSKA HIPOTEZA – ORIE 1961
Astma i HOBP su različite ekspresije iste bolesti sa preklapanjem
kliničkih sindroma: jedna forma može preći u drugu
Bronhijalna inflamacija
Bronhijalna hiperreaktivnost
Genetska
predispozicija
Faktori
sredine
Alergija, infekcija,
pušenje, zagađenje
ASTMA
HOBP
Bleecker ER. Chest. 2004; 126:93S-95S.
Sluiter HJ, et al. Eur Respir J. 1991; 4(4):479-489.
4. ATS: STANDARDI ZA HOBP 1995
RAZDVAJANJE ASTME I HOBP
Hronični bronhitis
Emfizem
Astma
5. DEFINICIJA ASTME, GINA 2012
Astma je hronična inflamatorna bolest disajnih puteva u kojoj
mnoge ćelije i ćelijski elementi igraju ulogu.
Hronična upala je povezana sa hiperreaktivnošću disajnih
puteva koja dovodi do ponavljanih epizoda otežanog disanja,
zviždanja, stezanja u grudima i kašlja, posebno noću ili u ranim
jutarnjim satima. Ove epizode obično su povezane sa
rasprostranjenom, ali varijabilnom opstrukcijom koja je često
reverzibilna spontano ili uz lečenje.
From the Global Strategy for Asthma Management and Prevention, Global Initiative for Asthma (GINA) 2012.
6. DEFINICIJA HOBP, GOLD 2011
HOBP, obično bolest koja se može sprečiti i lečiti,
karakteriše se perzistentno ograničenim protokom
vazduha u disajnim putevima koje je obično
progresivno i udruženo sa povišenim hroničnim
inflamatornim odgovorom u disajnim putevima i
plućima na štetne čestice i gasove.
Egzacerbacije i komorbiditeti doprinose ukupnoj težini
kod pojedinih pacijenta.
From the Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2013.
9. KLINIČKI FENOTIPOVI HOBP
Fenotip u HOBP:
Jedna ili kombinacija više osobina koje opisuju razliku između osoba sa
HOBP, jer se odnose na klinički značajne ishode
o Overlap sindrom – mešoviti HOBP-astma fenotip
o Česti pogoršivač fenotip
o Emfizem-hiperinflacija fenotip
Miravitlles M, Myriam Calle et al. Arch Bronconeumol. 2012;48:86-98.
11. PROPORCIONALNIVENOV DIJAGRAM
OPSTRUKTIVNIH BOLESTI PLUĆA U SAD,
STARIJI OD 8 GODINA
Soriano JB, et al. CHEST. 2003;124(2):474-481.
Astma 5.5% Hronični bronhitis 3.2% Emfizem 1.5%
NHANES III
U Srbiji 2007. godine
~ 370 000 osoba sa HOBP
5% populacije
12. INCIDENCA PREKLAPANJA ASTME I HOBP
620 pacijenata sa dijagnozom HOBP, funkcionalnim testiranjima i istorijom lečenja
Pracharova S, et al. ERS 19th Annual Congress: Abstract 4562. 2009
28
188
206
198
AB
(216)
HOBP
(394)
OVERLAP
SINDROM
BEZ
OPSTRUKCIJE
30%SA OVERLAP SINDROMOM
13. FENOTIPOVI U HOBP
WELLINGTON RESPIRATORY SURVEY
469 ispitanika starijih od 50 godina, 92 sa HOBP
Marsh SE., Travers J. et.al. Thorax 2008:63:761-767.
55%SA OVERLAP SINDROMOM
HOBP
14. OVERLAP SINDROM U ADULTNOJ
POPULACIJI
70
60
50
40
30
20
10
0
40-49 50-59 60-69 70-79 >80
Starost
Procenat pacijenata
sa overlap sindromom
Gibson PG , Simpson JL. Thorax. 2009;64:728-735
Muškarci
Žene
16. Soler-Cataluna J.J, Cosio B. et.al.Arch Bronconeumol. 2012;48(9):331–337
2 MAJOR KRITERIJUMA ili 1 MAJOR + 2 MINOR
MAJOR KRITERIJUMI
Vrlo pozitivan BDT (> 400 ml i > 15%
FEV1)
Sputum eozinofilija
Prethodna dijagnoza astme
MINOR KRITERIJUMI
Povećan ukupni serumski IgE
Ranija istorija atopije
Pozitivan BDT (> 200ml i > 12%
FEV1) na najmanje dve posete
POSTAVLJANJE DIJAGNOZE
18. ŠPANSKIVODIČ ZA LEČENJE HOBP 2012
Recommendations OfThe Spanish Society Of PulmonologyAndThoracic Surgery
Miravitlles M, et al.Arch Bronconeumol. 2012;48(7):247–257.
19. Nemamo studije koje se bave ovim pacijentima
Lošiji kvalitet života
Brže propadanje disajne funkcije
Češća i teža pogoršanja
Lečenje?
20. OVERLAP SINDROM I KVALITET ŽIVOTA
COPDGene study, 915 pacijenata sa HOBP, 119 sa mešovitim fenotipom
KLINIČKI ZNAČAJNA RAZLIKA U KVALITETU ŽIVOTA ( ΔSGRQ=5.2)
1546 pacijenata sa astmom, HOBP ili astma+HOBP
PACIJENTI SA OVERLAP SINDROMOM IMAJU NAJLOŠIJI KVALITET ŽIVOTA
Rizik za nizak HRQol u odnosu na astmatičare: OR 1.9 (95% confidence interval (CI): 1.2–3.2)
Hardin M, et al. Respir Res. 2011; 12(1): 127.
Kauppi P, et al. Journal of Asthma. 2011; 48(3): 279-85.
21. OVERLAP SINDROM I PROPADANJE
DISAJNE FUNKCIJE
Gibson PG , Simpson JL. Thorax. 2009;64:728-735
RIZICI:
Pušenje
BHR
Astma
Pogoršanja
22. OVERLAP SINDROM I DISAJNA FUNKCIJA
THIRD NATIONAL HEALTH AND NUTRITION EXAMINATION SURVEY (NHANES III)
1988-1994
N= 20 050
Mannino DM, et al. Arch Intern Med. 2000;160(11):1683-1689.
23. OVERLAP SINDROM I POGORŠANJA
0
5
10
15
20
25
30
35
40
45
ČESTA POGORŠANJA
HOBP
18%
HOBP+ASTMA
42.7%
Hardin M, et al. Respir Res. 2011; 12(1): 127.
N= 915
p < 0.0001
24. OVERLAP SINDROM I POGORŠANJA
0
5
10
15
20
25
30
35
40
TEŠKA POGORŠANJA
HOBP
17.6%
HOBP+ASTMA
32.8%
Hardin M, et al. Respir Res. 2011; 12(1): 127.
N= 915
p < 0.0001
26. SEPAR PREPORUKE
Lečenje se započinje IKS/LABA bez obzira na vrednosti FEV1
Doze IKS se mogu stepenovati prema potrebi
Kod težih formi LAMA + IKS/LABA (Welte et al)
Teofilin (teže forme)
Roflumilast (hronični bronhitis)
Oprezno sa ukidanjem IKS-moguća pogoršanja
Miravitlles M, et al.Arch Bronconeumol. 2012;48(7):247–257.
Soler-Cataluna J.J, Cosio B. et.al.Arch Bronconeumol. 2012;48(9):331–337
27. TERAPIJSKE OPCIJE U OVERLAP SINDROMU
Aryal S, et al. European Respiratory Disease, 2011;7(2):101–105
• Prestanak pušenja
• IKS/LABA +/- LAMA
• LTRA?
• Pulmološka rehabilitacija
• Oksigenoterapija
• Vakcinacije
28. ZAŠTO JE MEŠOVITI FENOTIP BITAN?
Kanadske preporuke: “ ukoliko je komponenta astme (u HOBP)
naglašena, rano uvođenje IKS može da bude opravdano”.
Japanski vodič ima posebno poglavlje “Terapija HOBP komplikovane
astmom”
Španski vodič lečenje HOBP bazira prema fenotipovima, mešoviti
fenotip je jedan od njih
PERSONALIZOVANO LEČENJE PREMA FENOTIPU,
A NE PREMATEŽINI OPSTRUKCIJE
Piras B, Miravitlles M. Multidisciplinary Respiratory Medicine 2012, 7:8
29. CILJEVI LEČENJA MEŠOVITOG FENOTIPA
REDUKCIJA HRONIČNIH SIMPTOMA BOLESTI
REDUKCIJA UČESTALOSTI ITEŽINE POGORŠANJA
POPRAVLJANJE PROGNOZE
Ostvarivanje i kratkoročnih i dugoročnih ciljeva
Miravitlles M, et al. Arch Bronconeumol. 2012;48(7):247–257.
36. FIKSNE KOMBINACIJE I JUTARNJE
AKTIVNOSTI
Partridge MR et al. Ther Adv Respir Dis.2009; 3(4): 147-157.
0.30
0.25
0.20
0.15
0.10
0.05
0
okupati se obrisati se obući se doručkovati rana šetnja kasna šetnja
BUD/FORM 320/9 μg b.i.d.
SAL/FLU 50/500 μg b.i.d.
†
†
promenauvrednostimaCDLMupitnika
nakonuvođenja
† p ˂ 0.02
N=442
FEV1≤50%
37. UTICAJ FIKSNIH KOMBINACIJA NA
JUTARNJE AKTIVNOSTI
Partridge MR et al. Ther Adv Respir Dis.2009; 3(4): 147-157.
0.25
0.20
0.15
0.10
0.05
0
Salmeterol +
Fluticasone
50 + 500 μg
Budesonide +
Formoterol
320 + 9 μg
Minimalno
značajna
promena
(MID)
promenauvrednostimaCDLMupitnikanakonuvođenja
Brži početak delovanja i
veće unapređenje
jutarnjih aktivnosti u
odnosu na Sal/Flu uz
niže doze IKS...
N=442
FEV1≤50%
p ˂ 0.05
42. UTICAJ LABA NA KVALITET ŽIVOTA U HOBP
Sin DD et al. JAMA. 2003;290(17):2301-2312.
-8.0 -6.0 -4.0 -2.0 0 2.0 4.0-10.0 6.0 8.0 10.0
SGRQ
Reference
Wadbo et al, 2002
Chapman et al, 2002
Jones et al, 1997
Rossi et al, 2002
Dahl et al, 2001
Overall
Promena SGRQ vs placebo
SGRQ 2.8 jedinica poboljšanje
vs placebo
43. *Merenje upotrebom St. Georges RespiratoryQuestionnaire, potvrđenog sredstva merenja zdravstvenog statusa u HOBP
1. Calverley et al. Eur Respir J 2003;22:912-9 2. Szafranski et al. Eur Respir J 2003;21:74-81. 3. Calverley et al. Lancet 2003;361:449-56. 4. Calverley et al. N Engl J Med 2007;356:775-89.
–8
–7
–6
–5
–4
–3
–2
–1
0
∆zdravstveni
status
Klinički
značajno
poboljšanje
Budesonid/
formoterol1
Budesonid/
formoterol2
Salmeterol/
fluticasone
DPI3
Salmeterol/
fluticasone
DPI4
UTICAJ FIKSNIH KOMBINACIJA NA
KVALITET ŽIVOTA
44. SYMBICORTVEĆ U PRVOJ NEDELJI ZNAČAJNO
POPRAVLJA SIMPTOME U ODNOSU NA LABA
Szafranski W, et al. Eur Respir J 2003; 21:74–81.
*P < 0.001 vs. LABA
Prosečnapromenasimptomskoravs.placebonakon
7danaterapije
–0.05
–0.10
–0.20
–0.25
–0.30
Stezanja u
grudima
0
-0.15
Noćna
buđenja
Nedostatak
daha
Kašalj
Formoterol
Symbicort
45. SYMBICORT ZNAČAJNO UNAPREĐUJE
KVALITET ŽIVOTAVEĆ U PRVE 4 NEDELJE
Bourbeau J, et al. Eur Respir J 2005;26(Suppl 49):296s.
Symbicort dovodi do klinički relevantnog poboljšanja SGRQ skora već u prve 4 nedelje
tretmana pacijenata sa umerenom ili teškom HOBP
–8
–7
–6
–5
–4
–3
–2
–1
0
Aktivnost UticajSimptomi Ukupno
Klinički
značajno
poboljšanje
∆Zdravstveni
status
Pacijenti na Symbicortu
46. SYMBICORT UNAPREĐUJE KVALITET
ŽIVOTA SVIH 12 MESECI
Calverley PM, et al. Eur Respir J 2003; 22:912–919.
Placebo
Budesonide
Formoterol
Symbicort
-3
-1
1
3
4
6
-2
0
2
5
0 2 4 6 8 10 12
vreme nakon randomizacije (meseci)
-0.5
7.5 bodova
poboljšanje
vs placebo
***
*
**
**p<0.01 vs placebo
*p<0.05 vs placebo
***p<0.001 vs placebo
p=0.014 Symbicort vs formoterol
47. Tolerancija fizičkog napora
Symbicort dovodi do klinički značajnog popravljanja
tolerancije na napor u odnosu na formoterol i placebo
14% vs.formoterol
28%vs.placebo
Worth H, Förster K, Eriksson G, Nihlén U, Peterson S, Magnussen H. Budesonide added to formoterol contributes to improved exercise tolerance in patients with COPD. Respir Med. 2010;104(10):1450-9.
n=111 FEV1= 38%
EET=Exercise EnduranceTime
75% peak work capacity
cycle ergometry
1hr and 6hr postdose
0
20
40
60
80
100
120
EET 1h nakon jutarnje doze EET 6h nakon jutarnje doze
BUD/FORM vs. placebo BUD/FORM vs. FORM FORM vs. placebo
EET razlika u tretmanima (s)
49. EFIKASNOST LABA U PREVENCIJI
POGORŠANJA U HOBP
Sin DD et al. JAMA. 2003;290(17):2301-2312.
0 0.5 1.0 1.5 2.0 2.5 3.0
Relative Risk
Reference
Wadbo et al. 2002
Van Noord et al. 2000
Chapman et al. 2002
Rossi et al. 2002
Dahl et al. 2001
Aalbers al. 2002
Overall
Favors LABA Favors Placebo
RR= 0.79
95% CI = 0.69 to 0.90
50. EFIKASNOST U PREVENCIJI POGORŠANJA
NE ODREĐUJE DOZA IKS U FIKSNOJ KOMBINACIJI
0
20
40
60
80
100
SAL/FP 250/50 SAL/FP 500/50
%Pacijenatasa
pogoršanjima
SAL/FP Placebo Salmeterol FP
FDA Pulmonary and Allergy Drugs Advisory Committee. 2002
51. DOZA IKS U FIKSNOJ KOMBINACIJI NE MODIFIKUJE
UČESTALOST POJEDINIHTIPOVA POGORŠANJA
FDA Pulmonary and Allergy Drugs Advisory Committee. 2002
0
20
40
60
80
100
SAL/FP 250/50 SAL/FP 500/50
%pacijenatasa
um./teškimpogoršanjima
SAL/FP Placebo Salmeterol FP
52. TRISTAN – EFIKASNOST FIKSNE
KOMBINACIJE U PREVENCIJI POGORŠANJA
-14
-12
-10
-8
-6
-4
-2
0
Pogoršanja(%redukcije)
Sal/Flu
vs.
Sal
Sal/Flu
vs.
Flu
-7% -7%
Calverley P et al. Lancet 2003;361:449-56
∆SGRQ
Sal/Flu vs. placebo
-2.2p = NS for SAL/FLU vs components
n=1465
t=12 meseci
53. TORCH – EFIKASNOST FIKSNE
KOMBINACIJE U PREVENCIJI POGORŠANJA
-14
-12
-10
-8
-6
-4
-2
0
Pogoršanja(%redukcije)
Sal/Flu
vs.
Sal
Sal/Flu
vs.
Flu
-12%
-9%
Calverley PMA et al. N Engl J Med 2007;356:775-89
∆SGRQ
Sal/Flu vs. placebo
-3
n=6112
t=36 meseci
p = 0.002 SAL/FLU vs SAL
p = 0.024 SAL/FLU vs FLU
54. EFIKASNOST SYMBICORTA U PREVENCIJI
POGORŠANJA HOBP
*
*
*
*
* *
$
$
$
$
$ $
PLB
F
B
BFC320/9
PLB
F
B
BFC320/9
PLB
F
B
BFC160/9
BFC320/9
PLB
F
BFC160/9
BFC320/9
Szafranski Calvery Tashkin Rennard
Godišnjastopapogoršanja
2
1.8
1.6
1.4
1.2
1
0.8
0.6
0.4
0.2
0
-23% -30% -25% -25%
vs.FORMOTEROL
Sharafkhaneh A et al. International Journal of Chronic Obstructive Pulmonary Disease 2010:5 357–366
55. EFIKASNOST FIKSNIH KOMBINACIJA U
PREVENCIJI POGORŠANJA - NNT
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
Symbicort vs Formoterol Seretide vs Placebo
Broj neophodnih tretmana u prevenciji
1 pogoršanja
Calverley PMA et al. Eur Respir J 2003;22:912-9.
Calverley PMA et al. N Engl J Med 2007;356:775-89.
NNT= 2.1
NNT= 4
56. Blais L et al. Clin Ther.2010;32:1320–1328
Rate of exacerbations/patient/year
POGORŠANJA Adjusted RR 0.88(0.76 to 1.00) (95%Cl)
Rate of ED visits/patient/year
HITNE INTERVENCIJE Adjusted RR 0.75(0.58 to 0.97) (95%Cl)
Rate of hospitalizations/patient/year
HOBP hospitalizacije Adjusted RR 0.61(0.47 to 0.81) (95%Cl)
Claims for a prescription of tiotropiumPotreba za uvođenjem
tiotropijuma u terapiju Adjusted RR 0.71(0.57 to 0.89) (95%Cl)
®
PacijentisaHOBP
N=2262
T=12meseci
DIREKTNO POREĐENJE
SYMBICORTA I SERETIDEA U EFIKASNOSTI
57. PATHOS STUDIJA
rani rezultati
11 godina praćenja lečenja HOBP u primarnoj zaštiti u Švedskoj, 1999-2011
Retrospektivna, observaciona, populaciona studija koja je pratila razvoj zdravstvene
nege pacijenata sa HOBP, mortalitet, komorbiditete, efikasnost i bezbednost
N=21 361 pacijenata sa HOBP, 68 godina starosti prosečno
REZULTATI:
sve više se dijagnoza postavlja u primarnoj zaštiti ( 59% u 1999, 81% u 2009)
Dijagnoza se postavlja u ranijem životnom dobu (sa 73 god u 1999, 66 u 2009.)
LABA/IKS i tiotropijum sa rastom propisivanja
Učestalost pogoršanja ima trend opadanja (3.0 /pac/god na 1.3 /pac/god)
Study Report Summary. 2012
58. PATHOS STUDIJA
rani rezultati
9 893 pacijenata uključeno u subanalizu
7155 na For/Bud i 2738 na Sal/Flu
Ukupno 19 170 pacijent-godina
27% manji rizik od pogoršanja/pacijent/godini na For/Bud
(p˂ 0.001)
73% veća učestalost pneumonija na Sal/Flu terapiji
(p˂ 0.001)
Study Report Summary. 2012
59. Halpin DM et al. Int J Clin Pract. 2011;65(7):764-774.
PNEUMONIA AE
PNEUMONIA SAE
PNEUMONIA-RELATED
MORTALITY
AE = nezeljeni dogadjaj
SAE = ozbiljan nezeljeni dogadjaj
OR0.47(0.28 to 0.8) (95%Cl)
OR0.41(0.19 to 0.86) (95%Cl)
OR0.18(0.01 to 4.10) (95%Cl)
Analiza12RCT
SYMBICORT NOSI ZNAČAJNO MANJI RIZIK
OD PNEUMONIJE NASPRAM SERETIDEA
65. Mešoviti, HOBP-astma fenotip srećemo kod
20-40% naših pacijenata sa HOBP
Ovi pacijenti imaju izraženiju simptomatologiju,
češća pogoršanja i lošiju prognozu
IKS/LABA su osnova lečenja ovih pacijenata,
nevezano za vrednosti FEV1
Symbicort efikasno unapređuje kvalitet života u HOBP
Symbicort efikasno prevenira pogoršanja u HOBP
uz dobar bezbedonosni profil
Chest. 2004 Jul;126(1):59-65.Asthma as a risk factor for COPD in a longitudinal study.Silva GE, Sherrill DL, Guerra S, Barbee RA.SourceArizona Respiratory Center, University of Arizona, College of Medicine, Tucson, 85724, USA.AbstractBACKGROUND:For several years, asthma and COPD have been regarded as distinct entities, with distinct clinical courses. However, despite distinctive physiologic features at the time of diagnosis, and different risk factors, the two diseases over time may develop features that are quite similar.STUDY OBJECTIVE:To evaluate the association between physician-diagnosed asthma and the subsequent development of COPD in a cohort of 3,099 adult subjects from Tucson, AZ.DESIGN AND METHODS:A prospective observational study. Participants completed up to 12 standard respiratory questionnaires and 11 spirometry lung function measurements over a period of 20 years. Survival curves (with time to development of COPD as the dependent variable) were compared between subjects with asthma and subjects without asthma at the initial survey.RESULTS:Subjects with active asthma (n = 192) had significantly higher hazard ratios than inactive (n = 156) or nonasthmatic subjects (n = 2751) for acquiring COPD. As compared with nonasthmatics, active asthmatics had a 10-times-higher risk for acquiring symptoms of chronic bronchitis (95% confidence interval [CI], 4.94 to 20.25), 17-times-higher risk of receiving a diagnosis of emphysema (95% CI, 8.31 to 34.83), and 12.5-times-higher risk of fulfilling COPD criteria (95% CI, 6.84 to 22.84), even after adjusting for smoking history and other potential confounders.CONCLUSIONS:Physician-diagnosed asthma is significantly associated with an increased risk for CB, emphysema, and COPD.
Study objectives: The nonproportional Venn diagram of obstructive lung disease (OLD) produced for the 1995 American Thoracic Society guidelines has not been quantified. We aim to quantify the proportion of the general population with OLD and the intersections of physician-diagnosed asthma, chronic bronchitis, and emphysema in the United States and the United Kingdom, and to examine the relationship to obstructive spirometry.Design and participants: We analyzed data from the US National Health and Nutrition Examination (NHANES) III survey (1988 to 1994) and the UK General Practice Research Database for the year 1998.Results: The areas of intersection among the three OLD conditions produced seven mutually exclusive disease groups. The asthma-only group was the largest proportion of OLD patients, accounting for 50.3% and 79.4% of all OLD patients in the United States and the United Kingdom, respectively, and decreased with increasing age. Overall, 17% and 19% of OLD patients in the United States and in the United Kingdom, respectively, reported more than one OLD condition, and this percentage increased with age. According to the spirometry data from NHANES III, only 37.4% of emphysema-only patients had objective airflow obstruction. The prevalence of airflow obstruction was significantly higher among participants with combinations of emphysema and chronic bronchitis (57.7%), with emphysema and asthma (51.9%), and with all three OLD diseases concomitantly (52.0%).Conclusion: Concomitant diagnosis of asthma, chronic bronchitis, or emphysema is common among OLD patients from the general population, particularly in adults aged ≥ 50 years.
AbstractBackground: Chronic obstructive pulmonary disease (COPD) encompasses a group of disorders characterised by the presence of incompletely reversible airflow obstruction with overlapping subsets of different phenotypes including chronic bronchitis, emphysema or asthma. The aim of this study was to determine the proportion of adult subjects aged >50 years within each phenotypic subgroup of COPD, defined as a post-bronchodilator ratio of forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC) <0.7, in accordance with current international guidelines.Methods: Adults aged >50 years derived from a random population-based survey undertook detailed questionnaires, pulmonary function tests and chest CT scans. The proportion of subjects in each of 16 distinct phenotypes was determined based on combinations of chronic bronchitis, emphysema and asthma, with and without incompletely reversible airflow obstruction defined by a post-bronchodilator FEV1/FVC ratio of 0.7.Results: A total of 469 subjects completed the investigative modules, 96 of whom (20.5%) had COPD. Diagrams were constructed to demonstrate the relative proportions of the phenotypic subgroups in subjects with and without COPD. 18/96 subjects with COPD (19%) had the classical phenotypes of chronic bronchitis and/or emphysema but no asthma; asthma was the predominant COPD phenotype, being present in 53/96 (55%). When COPD was defined as a post-bronchodilator FEV1/FVC less than the lower limit of normal, there were one-third fewer subjects with COPD and a smaller proportion without a defined emphysema, chronic bronchitis or asthma phenotype.Conclusion: This study provides proportional classifications of the phenotypic subgroups of COPD which can be used as the basis for further research into the pathogenesis and treatment of this heterogeneous disorder.
AbstractINTRODUCTION:While it is known that asthma symptoms have a very variable pattern, the general belief is that the respiratory symptoms in COPD patients usually present little or no variability. Nevertheless, COPD patients report having "bad days". The objective of this present study was to evaluate the variability of the respiratory symptoms and their impact on the daily activities of a cohort of Spanish COPD patients.METHOD:We present the results of the Spanish patients who participated in a cross-sectional epidemiological study carried out in 17 European countries. Pulmonologists and Family Care physicians recruited patients with stable severe COPD (FEV1<50%). The perception of the patients on the variation in their symptoms was recorded by telephone interviews.RESULTS:A total of 472 patients provided data that was valid for analysis. Mean age was 68.6; 93% were men; mean FEV1(%) was 41%. 84.1% of the patients experimented at least one respiratory symptom in the previous week and 60.9% affirmed that their symptoms varied over the course of the day or week. The moment of the day when the symptoms were perceived to be more intense was during the morning.CONCLUSIONS:An important proportion of severe COPD patients perceive variability in their respiratory symptoms, with a greater intensity in the morning. The observation can have implications in treating patients with severe COPD as variability can be an initial sign of decompensation of the disease.
AbstractINTRODUCTION:While it is known that asthma symptoms have a very variable pattern, the general belief is that the respiratory symptoms in COPD patients usually present little or no variability. Nevertheless, COPD patients report having "bad days". The objective of this present study was to evaluate the variability of the respiratory symptoms and their impact on the daily activities of a cohort of Spanish COPD patients.METHOD:We present the results of the Spanish patients who participated in a cross-sectional epidemiological study carried out in 17 European countries. Pulmonologists and Family Care physicians recruited patients with stable severe COPD (FEV1<50%). The perception of the patients on the variation in their symptoms was recorded by telephone interviews.RESULTS:A total of 472 patients provided data that was valid for analysis. Mean age was 68.6; 93% were men; mean FEV1(%) was 41%. 84.1% of the patients experimented at least one respiratory symptom in the previous week and 60.9% affirmed that their symptoms varied over the course of the day or week. The moment of the day when the symptoms were perceived to be more intense was during the morning.CONCLUSIONS:An important proportion of severe COPD patients perceive variability in their respiratory symptoms, with a greater intensity in the morning. The observation can have implications in treating patients with severe COPD as variability can be an initial sign of decompensation of the disease.
AbstractChronic obstructive pulmonary disease (COPD) is a lung disease characterized with limitation of airflow that is not completely reversible, progressive deterioration of airways and systemic inflammation. This study has been planned to determine daily symptom variability of patients, expectations of patient and physicians from treatment and patient profiles. A total of 514 patients with COPD from 25 centers were included in this national, multicenter, cross-sectional observational study. Data regarding demographic features, concomitant diseases, history and treatment of COPD and expectations of patients and physicians were all obtained in a single visit. Mean [standard deviation (SD)] age of the patients was 64.1 (9.5) years; age range was 41-92 years, 50% of the patients were younger than 65 years and 91% were males. Educational level of the patients was at least primary school in 80.2%; and 54.3% (30.4%) of the patients had at least one concomitant disease, particularly a cardiovascular disease. Mean (SD) duration of having COPD was 5.4 (4.6) years. The majority of patients were at moderate (43.2%) and severe (35.0%) COPD stages and one or more exacerbations per year was determined in 71%. Inhaled beta-2 agonists (84.2%), inhaled steroids (76.3%) and inhaled long-acting anti-cholinergics (70.0%) were the most commonly used medications. Dyspnea (99.0%), sputum production (92.8%) and wheezing (90.5%) were the most common symptoms, and symptom variability for dyspnea (41.1%), sputum production (61.0%) and cough (53.5%) were seen the most in the morning hours (p< 0.001). Most commonly affected morning activity was climbing up/down the stairs (point of effect: 6.7), followed by wearing socks/shoes (point of effect: 4.3) and showering/bathing (point of effect: 4.2) by COPD. Major treatment expectations of patients were greater symptomatic relief (82.3%) and greater mobility (70.0%), faster symptomatic relief (61.1%) and improvement in morning activities (59.3%); while major treatment expectations of physicians included increased quality of life (100.0%) and decreased morbidity (96.0%). Quitting smoking was the most commonly recommended (88.3%) and implemented (67.9%) non-drug protective approach aimed at decreasing the frequency of exacerbations. Consequently, our results demonstrate that COPD is not a disease of only the elderly, is an important healthcare issue that often disrupt daily living of the patients due to inadequate disease awareness leading to overlooking of the symptoms by patient and physicians, and that a patient-centered approach based on the living standards, life expectancies and preferences of patients was crucial in patient management.
Effect on lung function and morningactivities of budesonide/formoterol versussalmeterol/fluticasone in patients with COPDMartyn R. Partridge, Wolfgang Schuermann, Ola Beckman, Tore Persson andTomasz PolanowskiAbstract:Background: Patients with chronic obstructive pulmonary disease (COPD) often experiencesymptoms and problems with activities early in the morning. This is the first study to comparethe effect of budesonide/formoterol and salmeterol/fluticasone on lung function, symptoms and activities early in the morning.Methods: Lung function (peak expiratory flow [PEF] and forced expiratory volume in 1 second[FEV1]) and symptoms were measured at bedside and activities were measured during themorning using a six-item questionnaire concerning basic morning routines. In a randomised, double-blind, multicentre, cross-over study, 442 patients with COPD aged 40 years (prebronchodilatorFEV1 50%; FEV1/vital capacity <70%) received budesonide/formoterol(320/9 mg, one inhalation twice daily) dry powder inhaler (DPI) or salmeterol/fluticasone(50/500 mg, one inhalation twice daily) DPI daily, for 1 week each, separated by a 1- to 2-weekwashout. Lung function (PEF and FEV1) shortly after rising from bed in the morning, symptomsand basic morning activities were assessed by electronic diary (e-Diary) recordings.Results: Budesonide/formoterol and salmeterol/fluticasone treatment increased morning PEF5 minutes post-dose, measured as a mean improvement from baseline over the full studyperiod (primary endpoint; adjusted mean change: 15.1 l/min and 14.2 l/min, respectively [difference 1.0 l/min; p¼0.603]). Mean morning FEV1 improved more following budesonide/formoterol treatment versus salmeterol/fluticasone at 5 minutes (0.12 l versus 0.09 l;p¼0.090) and 15 minutes (0.14 l versus 0.10 l; p<0.05) post-dose. Budesonide/formoteroldemonstrated a more rapid onset of effect as reflected by increases in e-Diary-recorded PEFand FEV1 from pre-dose to 5 and 15 minutes post-dose (all p<0.001) and spirometry at theclinic measured after the first dose (FEV1 p<0.001; 5 minutes post-dose). Improvements insymptom scores within 15 minutes after drug administration were similar for both drugs, butbudesonide/formoterol treatment resulted in significantly greater improvements in totalmorning activities score (getting washed, dried, dressed, eating breakfast and walking aroundthe home; 0.22 versus 0.12 respectively, p<0.05). Both treatments were well tolerated.Conclusions: Short-term treatment with budesonide/formoterol DPI or salmeterol/fluticasoneDPI was effective in patients with COPD. Budesonide/formoterol had a more rapid onset ofeffect compared with salmeterol/fluticasone and resulted in greater improvements in ability to perform morning activities despite the lower inhaled corticosteroid dose.
This study evaluated quality of life (QOL) as measured with the St. George's Respiratory Questionnaire (SGRQ) in 211 patients with COPD of different severities.Quality of life declined progressively with worsening COPD severity as defined by GOLD Stage.
AbstractBACKGROUND:Breathlessness and exercise intolerance frequently impact the daily life of patients with COPD.METHODS:This double-blind, multicentre, three-period crossover study randomised 111 patients with COPD (mean age 64 years, mean FEV(1) 38% of predicted normal) to budesonide/formoterol 320/9 microg, formoterol 9 microg or placebo, twice daily for 1 week, following a 1-week run-in period with 1-week wash-out between treatments. Terbutaline (0.5 mg/dose) was used as needed. The primary efficacy variable was exercise endurance time (EET) at 75% peak work capacity with cycle ergometry assessed 1 h post-morning dose.RESULTS:Budesonide/formoterol prolonged EET 1 h post-morning dose versus formoterol by 69 s (P < 0.005) and placebo by 105 s (P < 0.0001) and improved inspiratory capacity (IC) at isotime during exercise versus formoterol by 8% (P = 0.011) and placebo by 16% (P < 0.0001). Borg score at isotime was reduced by 0.48 (P = 0.12) and 0.78 (P = 0.014) compared with formoterol and placebo, respectively. At the repeated cycle test 6 h after morning dose, the effect on EET still favoured budesonide/formoterol over formoterol and placebo, while the isotime IC and Borg score were similar but better than placebo for the active study drugs. Budesonide/formoterol and formoterol improved health status (St George's Respiratory Questionnaire total score: mean difference versus placebo -2.4 and -2.2, respectively). All treatments were well tolerated.CONCLUSIONS:Budesonide/formoterol resulted in a significant improvement in endurance time 1 h after the last morning dose in a 1-week treatment period versus formoterol and placebo. This study demonstrates, for the first time, the benefit of inhaled corticosteroids in addition to long-acting beta(2)-agonists on exercise tolerance in COPD patients. www.clinicaltrials.gov registration number: NCT00489853.
BackgroundInhaled longacting â2 agonists improve lungfunction and health status in symptomatic chronic obstructivepulmonary disease (COPD), whereas inhaled corticosteroidsreduce the frequency of acute episodes of symptomexacerbation and delay deterioration in health status. Wepostulated that a combination of these treatments would bebetter than each component used alone.Methods1465 patients with COPD were recruited fromoutpatient departments in 25 countries. They were treated in arandomised, double-blind, parallel-group, placebo-controlledstudy with either 50 ìgsalmeterol twice daily (n=372), 500 ìgfluticasone twice daily (n=374), 50 ìgsalmeterol and 500 ìgfluticasone twice daily (n=358), or placebo (n=361) for12 months. The primary outcome was the pretreatment forcedexpiratory volume in 1 s (FEV1) after 12 months treatment’ andafter patients had abstained from all bronchodilators forat least 6 h and from study medication for at least 12 h.Secondary outcomes were other lung function measurements,symptoms and rescue treatment use, the number ofexacerbations, patient withdrawals, and disease-specifichealth status. We assessed adverse events, serum cortisolconcentrations, skin bruising, and lectrocardiograms.Analysis was as predefined in the study protocol.FindingsAll active treatments improved lung function,symptoms, and health status and reduced use of rescuemedication and frequency of exacerbations. Combinationtherapy improved pretreatment FEV1 significantly more than didplacebo (treatment difference 133 mL, 95% CI 105–161,p<0·0001), salmeterol (73 mL, 46–101, p<0·0001), orfluticasone alone (95 mL, 67–122, p<0·0001). Combinationtreatment produced a clinically significant improvement inhealth status and the greatest reduction in daily symptoms. Alltreatments were well tolerated with no difference in thefrequency of adverse events, bruising, or clinically significantfalls in serum cortisol concentration.InterpretationBecause inhaled long-acting â2 agonists andcorticosteroid combination treatment produces bettercontrol of symptoms and lung function, with no greater riskof side-effects than that with use of either component alone,this combination treatment should be considered for patientswith COPD.
BackgroundLong-acting beta-agonists and inhaled corticosteroids are used to treat chronic obstructive pulmonary disease (COPD), but their effect on survival is unknown.MethodsWe conducted a randomized, double-blind trial comparing salmeterol at a dose of 50 ìg plus fluticasone propionate at a dose of 500 ìg twice daily (combination regimen), administered with a single inhaler, with placebo, salmeterol alone, or fluticasone propionate alone for a period of 3 years. The primary outcome was death from any cause for the comparison between the combination regimen and placebo; the frequencyof exacerbations, health status, and spirometric values were also assessed.ResultsOf 6112 patients in the efficacy population, 875 died within 3 years after the start of the study treatment. All-cause mortality rates were 12.6% in the combinationtherapy group, 15.2% in the placebo group, 13.5% in the salmeterol group, and 16.0% in the fluticasone group. The hazard ratio for death in the combination-therapy group, as compared with the placebo group, was 0.825 (95% confidence interval [CI], 0.681 to 1.002; P = 0.052, adjusted for the interim analyses), corresponding to a difference of 2.6 percentage points or a reduction in the risk of death of 17.5%.The mortality rate for salmeterol alone or fluticasone propionate alone did not differ significantly from that for placebo. As compared with placebo, the combination regimen reduced the annual rate of exacerbations from 1.13 to 0.85 and improved health status and spirometric values (P<0.001 for all comparisons with placebo). There was no difference in the incidence of ocular or bone side effects. The probability of having pneumonia reported as an adverse event was higher among patients receiving medications containing fluticasone propionate (19.6% in the combination-therapy group and 18.3% in the fluticasone group) than in the placebo group (12.3%, P<0.001 for comparisons between these treatments and placebo).ConclusionsThe reduction in death from all causes among patients with COPD in the combinationtherapy group did not reach the predetermined level of statistical significance. There were significant benefits in all other outcomes among these patients. (ClinicalTrials.gov number, NCT00268216.)
AbstractAims: This analysis was designed to provide a comparison between budesonide/formoterol and salmeterol/fluticasone for the relative incidence of pneumonia adverse events, pneumonia serious adverse events and pneumonia-related mortality in patients being treated for chronic obstructive pulmonary disease.Methods: An initial literature search revealed no suitable head-to-head trials between budesonide/formoterol and salmeterol/fluticasone and therefore a systematic review was conducted to find randomised controlled trials providing data for input into an adjusted indirect comparison of the two combination treatments using placebo as a common comparator. The Bucher adjusted indirect comparison method was used to calculate odds ratios and 95% confidence intervals.Results: Eight salmeterol/fluticasone trials and four budesonide/formoterol trials were identified as being relevant for the analyses. The proportion of patients experiencing a pneumonia adverse event was significantly lower with budesonide/formoterol than salmeterol/fluticasone (odds ratio, 0.47; 95% confidence interval, 0.28–0.80). The proportion of patients experiencing a pneumonia serious adverse event was also significantly lower with budesonide/formoterol than salmeterol/fluticasone (odds ratio, 0.41; 95% confidence interval, 0.19–0.86). However, there were too few events to draw any firm conclusions on pneumonia-related mortality.Conclusions: The results of the indirect comparison support the hypothesis that budesonide/formoterol is associated with fewer pneumonia events than salmeterol/fluticasone in chronic obstructive pulmonary disease. The limitations of the analysis are that the results from a single study, TORCH, have a large bearing on the overall findings of the analysis, and that there is heterogeneity in the length and the dosing of the included studies, although it does not appear that heterogeneity affected the reported results. Another important limitation is the lack of predefined diagnostic standards for pneumonia in these studies.
Speaker NotesThis study of 449 patients with moderate-to-severe COPD was carried out to determine whether combining tiotropium with salmeterol or fluticasone-salmeterol improves clinical outcomes in adults with moderate to severe COPD compared with tiotropium alone. Study results showed that the proportion of patients in the tiotropium plus placebo group (62.8%) who experienced an exacerbation did not differ from that in the tiotropium plus salmeterol group (64.8%) or in the tiotropium plus fluticasone and salmeterol group (60.0%).Reference Aaron SD, Vandemheen KL, et al. Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease: a randomized trial. Ann Intern Med. 2007;146:545-555.
COPD symptoms and morning activities assessed by the CDLM QuestionnaireChanges in total morning activity score were more apparent after 1 week of treatment with budesonide/formoterol plus tiotropium compared with tiotropium alone (mean difference 0.074; p=0.027)These improvements were sustained to week 12 (mean difference 0.180; p<0.001) and continued to improve over the study periodThe CDLM Questionnaire is an eight-item questionnairePatients completed the CDLM questionnaire at home at midday, during weeks 1, 6 and 12 (for 7 consecutive days) of treatment, after performing all morning activitieswashingdressingeating breakfastwalking aroundFor an overview of the scales used, please refer to Appendix I (slide 35)
Time to first severe exacerbation and the number of severe exacerbations were measuredSevere exacerbations were defined as worsening of COPD requiring systemic corticosteroids (oral or parenteral) and/or hospital/emergency room visitsSevere exacerbations were experienced by25 patients (7.6%) in the budesonide/formoterol plus tiotropium group61 patients (18.5%) in the tiotropium alone groupBudesonide/formoterol plus tiotropium compared with tiotropium alonedecreased the rate of severe exacerbations by 62% (rate ratio 0.38, 95% CI 0.25, 0.57; p<0.001) prolonged the time to first severe exacerbation (hazard ratio 0.39, 95% CI 0.24, 0.62; p<0.001)57 patients required a prescription of antibiotics for the reason ‘exacerbation of COPD’19 (6%) in the budesonide/formoterol plus tiotropium group38 (12%) in the tiotropium alone groupThe use of antibiotics was not part of the definition of exacerbation in this study, however the use of antibiotics for worsening of COPD was lower in the budesonide/formoterol plus tiotropium group, indicating that the overall effect on exacerbations was not confounded by differences in antibiotic use between groups
