THE BENEFIT OF FLUTICASONE PROPIONATE /SALMETEROL XINAFOATE
IN COPD
SFC DATA IN COPD Short-term benefits
SFC reduces breathlessness in COPD from 1 day onwards
0
0.5
1.0
1.5
2.0
2.5
P lacebo (n=181)
Sa lmeterol 50μg bd (n=160)
SFC 50/250μg bd (n=165)
Impr
ovem
ent i
n br
eath
less
ness
sco
re
1.7 1.2
*
* p<0.001 vs placebo and salmeterol. Differences vs placebo and salmeterol exceed the clinically relevant difference threshold of 1 unit for this index. Patients were allowed as-needed salbutamol and stable regimens of theophylline could be continued Mahler Am J Respir Crit Care Med 2002
SFC improves FEV1 in COPD from 1 week onwards
Mahler Am J Respir Crit Care Med 2002
p<0.001 SFC, salmeterol and FP vs placebo p=0.012 SFC vs salmeterol p=0.038 SFC vs FP
0
Salmeterol
SFC
Placebo
FP
0 2 4 6 8 12 16 20 24
Time (weeks)
200
150
100
50
–50 Mea
n ch
ange
in p
redo
se F
EV1 (
ml)
SFC DATA IN COPD Long-term benefits
Anti-inflammatory effects of SFC in COPD: reduction in CD8+ T-lymphocytes
Placebo (n=69) SFC (n=55)
0 40 80
120 160 200 240 280 320
Med
ian
cells
/mm
2
Bas e line Week 12 Bas e line Week 12
p=0.015
In a placebo-controlled 3-month biopsy study SFC 50/500μg bd was shown to have a broad range of anti-inflammatory effects that may help explain its clinical effects
Barnes Am J Respir Crit Care Med 2006
TORCH: study design
SFC 50/500μg bd n=1533
Sa lmeterol 50μg n=1521
P lacebo n=1524
FP 500μg bd n=1534
2-week run-in
All doses taken in the morning and evening for 3 years Calverley N Eng J Med 2007
Primary endpoint: The effect of SFC 50/500 mg vs placebo on all-cause mortality over 3 years in patients with moderate-to-severe COPD Secondary endpoints: The effect of SFC 50/500 mg on the rate of moderate and severe exacerbations; The effect of SFC 50/500 mg on health status (SGRQ)
Vertical bars are standard errors
18 16 14 12 10
8 6 4 2 0
Time to death (weeks)
Probability of death (%)
1524 1533 1521 1534
1464 1487 1481 1487
1399 1426 1417 1409
1293 1339 1316 1288
Placebo Salmeterol FP SFC
Number alive
0 12 24 36 48 60 72 84 96 108 120 132 144 156
HR, 0.825 (95% CI, 0.681–1.002)
p=0.052 (log-rank test)
Trend towards reduction in all-cause mortality at 3 years
Calverley N Eng J Med 2007
1350
1300
1250
1200
1150
1100
SFC slows the rate of decline of lung function over 3 years
FEV 1
(ml)
0 24 48 72 96 120 156 Weeks
–39 ml/yr
– 42 ml/yr
– 55 ml/yr
– 42 ml/yr
Placebo Salmeterol FP SFC
SFC versus placebo: 16 ml/yr, p<0.001 Salmeterol versus placebo: 13 ml/yr, p=0.003 FP versus placebo: 13 ml/yr, p=0.003
Celli BR. Am J Respir Crit Care Med 2008
0.02 9% SFC vs FP 0.002 12% SFC vs salmeterol
<0.001 25% SFC vs p lacebo
SFC significantly reduces exacerbations over 3 years
p-va lue Trea tment e ffec t
0
0.2
0.4
0.6
0.8
1.0
1.2
P lacebo
Ann
ualis
ed e
xace
rbat
ion
rate
S a lmeterol FP SFC
25% (p<0.001)
1.13
0.97 0.93 0.85
Calverley N Eng J Med 2007
SFC significantly improves in quality of life
Vertical bars represent standard errors
p-value
SFC vs FP
SFC vs placebo
– 1.2 units – 2.2 units –3.1 units
Treatment diff
0.02 <0.001 <0.001
SFC vs salmeterol
Placebo
Salmeterol
FP
SFC
Calverley N Eng J Med 2007
4 3 2 1 0
– 1 – 2 – 3 – 4 – 5 – 6
Adju
sted
mea
n ch
ange
SG
RQ
tota
l sco
re
0 24 48 72 96 120 156 Time (weeks)
impr
ovem
ent
Stratification by GOLD stage
N (%) patients in group GOLD stage Placebo
(n= 1524) Salmeterol (n=1521)
FP (n=1534)
SFC (n=1533)
Total (n=6112)
IV – Very severe FEV1 <30% 214 (14) 260 (17) 220 (14) 243 (16) 937 (15)
III - Severe FEV1 30% to <50%
775 (51) 739 (49) 777 (51) 728 (47) 3019 (49)
II/I – Moderate/ mild FEV1 ≥ 50%
535 (35) 522 (34) 537 (35) 562 (37) 2156 (35)
Jenkins et al. Respir Res 2009
All-cause mortality by baseline % predicted post-bronchodilator FEV1
Patien t (N) 214 260 220 243 775 739 777 728 535 522 537 562 Death (N) 52 64 53 43 118 93 140 106 61 48 53 44
Brackets s how hazard ra tio (95% CI) for ris k of dea th for SFC vs p lacebo Jenkins et al. Respir Res 2009
Prob
abili
ty o
f mor
talit
y (%
)
% FEV1 at baseline <30% 30% to <50% ≥50%
HR 0.70 (0.47, 1.05)
HR 0.67 (0.45, 0.98)
HR 0.95 (0.73, 1.24)
0
5
10
15
20
25
30
Exacerbation rate by baseline % predicted post-bronchodilator FEV1
14% (-4, 29)
Brackets show % reduction (95% CI) of exacerbations rate for SFC vs placebo Jenkins et al. Respir Res 2009
Rat
e of
mod
erat
e/se
vere
exa
cerb
atio
ns
<30% % FEV1 at baseline
30% to <50% ≥50%
31% (19, 40)
26% (17, 34)
0.8
1.2
1.4
1.6
1.8
2.0
0
0.2
0.4
0.6
Improvement (reduction) in SGRQ vs placebo by baseline % predicted post-bronchodilator FEV1
Adju
sted
mea
n ch
ange
in S
GR
Q
tota
l sco
re
<30% 30% to <50% ≥50% % FEV1 at baseline
Bas e line SGRQ s core 57.5 54.6 55.3 56.4 49.8 49.5 50.8 48.8 43.9 47.2 45.1 45.2
-5.0 (-8.7, -3.0)
-2.3 (-4.0, 0.7) -3.3 (-4.7, -1.9)
Brackets s how adjus ted mean (95% CI) d iffe rence of SFC vs p lacebo Jenkins et al. Respir Res 2009
Rate of decline in FEV1 by baseline % predicted post-bronchodilator FEV1
Adju
sted
rate
of d
eclin
e in
FE
V 1 (m
l/yea
r)
<30% 30% to <50% ≥50%
% FEV1 at baseline
Bas e line FEV1 (ml) 717 709 713 707 1108 1137 1101 1113 1634 1587 1635 1625
11 (-8, 30)
16 (5, 28) 16 (0, 32)
Brackets s how adjus ted mean (95% CI) d iffe rence of SFC vs p lacebo Jenkins et al. Respir Res 2009
INSPIRE: study design
The INSPIRE study is the first head-to-head trial to compare SFC 50/500μg Accuhaler/Diskus™ with tiotropium bromide
The study aimed to assess the effect of SFC vs tiotropium in reducing the rate of healthcare utilisation, COPD exacerbations and related outcomes over 104 weeks in patients with severe COPD
Prednisolone 30 mg/day Salmeterol 50μg bd Tiotropium 18μg qd (n=665)
SFC 50/500μg Accuhaler/Diskus bd (n=658)
1499 patients were screened and 1323 were randomised
2-week run-in
Wedzicha et al. Am J Crit Care Med 2008
SFC healthcare utilisation exacerbation rates
Wedzicha et al. Am J Crit Care Med 2008
Tiotropium 18μg
1.28 1.32
0.69 0.85 0.97
0.82
p=0.039
0
0.5
1
1.5
2
2.5
3
3.5
Exac
erba
tion
rate
m
ean/
year
Healthcare utilisation exacerbations
Healthcare utilisation exacerbations
requiring antibiotics
Healthcare utilisation exacerbations requiring
oral corticosteroids
p=0.656 p=0.028
SFC 50/500μg
SFC: significant and sustained improvements in quality of life
–2.1-unit difference in total SGRQ score (p=0.038) at wk 104
55
–2
50
45
40
0 10 22 34 46 58 70 82 94 106
Time (weeks )
SG
RQ
tota
l sco
res
(uni
ts)
Tiotropium 18μg SFC 50/500μg
Wedzicha et al. Am J Crit Care Med 2008
SFC improved survival over 2 years vs tiotropium
Pro
babi
lity
of d
eath
(%)
0
1
2
3
4
5
6
7
8
Time to dea th (weeks ) 0 13 26 39 52 65 78 91 104
52% relative risk reduction with SFC vs tiotropium (p=0.012)
INSPIRE showed a significant reduction in all-cause mortality with SFC vs tiotropium over 2 years (p=0.012)
Wedzicha et al. Am J Crit Care Med 2008
Tiotropium 18μg SFC 50/500μg
Time to withdrawal: more subjects withdraw from the tiotropium arm
Probability of withdrawal prior to wk 104 SFC 34.5% Tio 41.7%
658 560 531 510 494 476 456 445 160 SFC 50/500 665 547 501 474 450 434 415 397 140 Tio 18
0 13 26 39 52 65 78 91 104
Number a t ris k
0
4
8
12
16
20
24
28
32
36
40
44
Pro
babi
lity
of e
vent
(%)
Time to event (weeks )
Wedzicha et al. Am J Crit Care Med 2008
Tiotropium 18μg SFC 50/500μg
SFC DATA IN COPD Safety
Most common reported AEs (started during treatment)
SFC (n=1546)
COPD exacerbations
FP (n=1552)
Sa lmete ro l (n=1542)
Placebo (n=1544)
0.92 0.76 0.78 0.67
Upper respiratory tract infection 0.10 0.08 0.09 0.11 Nasopharyngitis 0.09 0.09 0.10 0.10
Pneumonia 0.04 0.04 0.07 0.07
Bronchitis 0.05 0.05 0.05 0.05
Headache 0.08 0.06 0.06 0.05
Back pain 0.04 0.04 0.04 0.04
Sinusitis 0.03 0.03 0.04 0.04
Cough 0.03 0.03 0.04 0.03
Hypertension 0.03 0.03 0.03 0.02
Rate per treatment year
Calverley N Eng J Med 2007
Placebo (n=1544)
Sa lmetero l (n=1542)
FP (n=1552)
SFC (n=1546)
Patients with pneumonia (n) 139 162 224 248
Probability* of pneumonia by 3 years (%) 12.3 13.3 18.3 19.6
Probability of having Pneumonia
*Kaplan-Meier estimate of probability
HR 95% CI p-va lue
SFC vs placebo 1.64 (1.33, 2.02) <0.001
FP vs placebo 1.53 (1.24, 1.89) <0.001
Salmeterol vs placebo 1.09 (0.87, 1.37) 0.465
Crim et al. Eur Respir J 2009
Limitations of pneumonia data
Pneumonias were captured solely by AE reporting
There was no standardised procedure for the diagnosis or treatment of pneumonia
Chest x-rays, white blood cell count and cultures were not required for diagnosing pneumonia
When culture results were available for review, there was no evidence of opportunistic infections and the infectious agents identified were compatible with those expected in a COPD population
Crim et al. Eur Respir J 2009
Mortality from pneumonia
0.0032 0.0042 0.0031 0.0031 Fatal serious AE rate*
SFC (N = 1546)
FP (N = 1552)
SAL (N = 1542)
Placebo (N = 1544)
* Rate per treatment year
8 13 9 7 On-treatment deaths adjudicated by Clinical Endpoint Committee
1. Calverley PMA et al. NEJM 2007
Pneumonia summary Both SFC and FP were associated with an increased reporting of
pneumonia compared with salmeterol and placebo1
The increase in reports of pneumonia as an AE in the ICS-containing treatment arms occurred despite a decrease in overall COPD exacerbations, of which pneumonia was a subset1
– The increase in reported pneumonias with SFC did not result in an increase in pneumonia-related deaths
Risk factors for pneumonia in all treatment groups were1
– older age – lower % predicted FEV1
– any COPD exacerbation in the year prior to the study – worse MRC dyspnoea score – lower BMI
Healthcare professionals should remain vigilant for the possible development of pneumonia and implement early and appropriate therapy
– signs and symptoms of COPD exacerbations and pneumonia often overlap2
1. Crim e t a l. Eur Res pir J 2009. 2. Lieberman e t a l. Ches t 2002
COPD: conclusions
Seretide offers significant benefits from day 1 onwards:1–5
– Improvement in lung function at 24 hours2,3
– Improvements in breathlessness at 2 days3
– Reduced rate of exacerbations over 3 years1
– Reduced rate of lung function decline over 3 years4
– Improvement in quality of life over 3 years1,5
1. Seretide UK SPC. 2. Dalal Chest 2009. 3. Vestbo Thorax 2005. 4. Celli Am J Respir Care Med 2008. 5. Calverley N Engl J Med 2007
TERIMA KASIH ATAS
PERHATIANNYA
Result of recent and existing data TOwards a Revolution in COPD Health
Investigating New Standards for Prophylaxis In Reduction of Exacerbations
The Understanding Potential Long-term Impacts on Function with Tiotropium
Study design : 3 yr, R, DB, C, 444 centers from 42 countries, 6112 pts
Study Design : 4 yr, R, DB, C, 487 centers from 37 countries, 5993 pts
SFC vs PBO
Tio vs PBO
Study Design : 2 yr, R, DB, DD, C, 179 centers from 20 countries, 1323 pts
SFC vs Tio
Background: Effects on FEV1 decline ICS/LABA1 & LAMA2 therapy
1. Celli B, et al. AJRCCM 2008;178:332-338 2. Tashkin D, et al. N Eng J Med 2008;359:1543-54
Salmeterol/Fluticasone propionate (50/500mcg) reduced rate of decline by 16 mL/year vs. placebo (p<0.001) Tiotropium (18mcg) reduced rate of decline by 2mL/year vs. placebo (p=0.21)
Permission applied for to reproduce figures
* * *
* *
* *
* *
* * * * *
* * * *
1.50
1.40
1.30
1.20
1.10
1.00
0 6 12 18 24 30 48 1 36 42 FE
V 1 (L
iters
) Month Day
30
After bronchodilation
Before bronchodilation
Tiotropium (N=2516)
Placebo (N=2374)
Tiotropium (N=2494)
Placebo (N=2363)
1350
1300
1250
1200
1150
1100
0 24 48 72 96 120 156
FEV 1
(mL)
Time (weeks)
-39 mL/yr
-42 mL/yr -42 mL/yr
-55 mL/yr
SFC
FP
PBO
SAL
www.ECLIPSE-copd.com
Impr
ovem
ent
SGR
Q T
otal
Sco
re (u
nits
) Placebo(n=2337)
Tiotropium(n=2478)
0
35
40
45
50
p=0.78
0 6 12 18 24 30 36 42 48
MonthIm
prov
emen
t
SGR
Q T
otal
Sco
re (u
nits
) Placebo(n=2337)
Tiotropium(n=2478)
0
35
40
45
50
p=0.78
0 6 12 18 24 30 36 42 48
Month
Tashkin DP et al. N Engl J Med 2008; 359: 1543–54.
CRM: Concomitant respiratory medication
Vertical bars represent standard errorsPlacebo Sal 50 FP 500 SFC
43210
-1-2-3-4-5-6
Adj
uste
d m
ean
chan
ge
SGR
Q to
tal s
core
0 24 48 72 96 120 156Time (weeks)
impr
ovem
ent
p-value
SFC vs FP
SFC vs placebo
-1.2 units-2.2 units-3.1 units
Treatment diff
0.02<0.001<0.001
SFC vs sal
Placebo
Sal 50
FP 500
SFC
Vertical bars represent standard errorsPlacebo Sal 50 FP 500 SFCPlacebo Sal 50 FP 500 SFC
43210
-1-2-3-4-5-6
43210
-1-2-3-4-5-6
Adj
uste
d m
ean
chan
ge
SGR
Q to
tal s
core
0 24 48 72 96 120 156Time (weeks)
impr
ovem
ent
p-value
SFC vs FP
SFC vs placebo
-1.2 units-2.2 units-3.1 units
Treatment diff
0.02<0.001<0.001
SFC vs sal
Placebo
Sal 50
FP 500
SFC
Calverley PMA et al. N Eng J Med 2007; 356: 775-789.
Improvement in QoL based on SGRQ
Salm/FP (50/500mcg) significantly improved QoL with the overall difference is 3.1 (vs placebo, over 3 years)
Tio (18mcg) not significantly improved QoL with the overall difference is 2.7( vs. Placebo, over 4 years)
0.029%SFC vs FP0.00212%SFC vs sal
<0.00125%SFC vs placebo
p-valueTreatment effect
0
0.2
0.4
0.6
0.8
1
1.2
Placebo
Ann
ualis
ed e
xace
rbat
ion
rate
Sal FP SFC
25% (p<0.001)
1.13
0.97 0.930.85
0.029%SFC vs FP0.00212%SFC vs sal
<0.00125%SFC vs placebo
p-valueTreatment effect
0
0.2
0.4
0.6
0.8
1
1.2
Placebo
Ann
ualis
ed e
xace
rbat
ion
rate
Sal FP SFC
25% (p<0.001)
1.13
0.97 0.930.85
Tashkin DP et al. N Engl J Med 2008; 359: 1543–54.
CRM: Concomitant respiratory medication Calverley PMA et al. N Eng J Med 2007; 356: 775-789.
Exacerbation and Related hospitalization
80
60
40
20
0
Prob
abili
ty o
f exa
cerb
atio
n (%
)
0 6 12 18 24 30 36 42 48
Month
Hazard ratio, 0.86(95% Cl, 0.81–0.91)p<0.001)
TiotropiumPlacebo
80
60
40
20
0
Prob
abili
ty o
f exa
cerb
atio
n (%
)
0 6 12 18 24 30 36 42 48
Month
Hazard ratio, 0.86(95% Cl, 0.81–0.91)p<0.001)
TiotropiumPlacebo
Salm/FP (50/500mcg) significantly reduced exacerbation over 3 years & reduced the rate of severe exacerbations requiring hospitalisation
Tio (18mcg) significantly reduced exacerbation over 4 years, however Tio did not significantly reduce the rate exacerbation requiring hospitalization
Tashkin DP et al. N Engl J Med 2008; 359: 1543–54. Calverley PMA et al. N Eng J Med 2007; 356: 775-789.
All cause mortality
FP
Vertical bars are standard errors
1816141210
86420
Time to death (weeks)
Mor
talit
y (%
)
1524153315211534
1464148714811487
1399142614171409
1293133913161288
Placebo SFC
Numberalive
0 12 24 36 48 60 72 84 96 108 120 132 144 156
SAL
17.5% risk reduction with SFC vs placebo (p=0.052)
FP
Vertical bars are standard errors
1816141210
86420
Time to death (weeks)
Mor
talit
y (%
)
1524153315211534
1464148714811487
1399142614171409
1293133913161288
Placebo SFC
Numberalive
0 12 24 36 48 60 72 84 96 108 120 132 144 156
SAL
17.5% risk reduction with SFC vs placebo (p=0.052)
20
15
10
5
0
Prob
abili
ty o
f dea
th fr
om
any
caus
e (%
)
0 1 2 3 4
Hazard ratio, 0.89(95% Cl, 0.79-1.02)
Tiotropium
Placebop<0.09
20
15
10
5
0
Prob
abili
ty o
f dea
th fr
om
any
caus
e (%
)
0 1 2 3 4
Hazard ratio, 0.89(95% Cl, 0.79-1.02)
Tiotropium
Placebop<0.09
Years
Mortality at 1470 days: Predefined secondary analysis
Salm/FP (50/500mcg) reduced the risk of all cause mortality by 17.5% over 3 years Tio (18mcg) reduced the risk of all cause mortality by 11% over 4 years
FEV1 Decline: ECLIPSE Decline by GOLD Category
GOLD 2 vs. GOLD 3, p=0.17; GOLD 2 vs. GOLD 4, p<0.001; GOLD 3 vs. GOLD 4, p=0.009
Rate of decline reduced with increasing disease severity Significantly less decline in GOLD 4 vs. GOLD 2 or 3
N Engl J Med. 2011 Sep 29;365(13):1184-92
Mortality from pneumonia
0.0032 0.0042 0.0031 0.0031 Fatal serious AE rate*
SFC (N = 1546)
FP (N = 1552)
SAL (N = 1542)
Placebo (N = 1544)
* Rate per treatment year
8 13 9 7 On-treatment deaths adjudicated by Clinical Endpoint Committee
1. Calverley PMA et al. NEJM 2007
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