Download Tiotropium

Apports de l’étude UPLIFT
Pr Michel Aubier
Service de Pneumologie A
Hôpital Bichat, Paris
Schéma de l’étude
• Etude Multi-nationale, multi-centrique, doubleaveugle, randomisée, traitement actif vs placebo,
groupes parallèles
• Comparaison en prospectif des 2 groupes sur une
période de 4 années de traitement
-Premier patient randomisé - Jan 2003
-Dernier patient sorti - Feb 2008
Co-Critères Primaires de jugement
•Pente de déclin annuel du VEMS prébronchodilatateur du jour 30 (steady state) jusqu’à
la terminaison du traitement en double aveugle
• Pente de déclin annuel du VEMS postbronchodilateur du jour 30 (steady state) jusqu’à la
terminaison du traitement en double aveugle
Critères secondaires de jugement
•Critère secondaire principal
– Temps jusqu’à la 1ère exacerbation
– Temps jusqu’à la 1ère hospitalisation
•Autres critères secondaires
– Critères spirométriques autres que les primaires
– Exacerbations de BPCO & hospitalisations
– HRQoL (St. George’s Respiratory Questionnaire)
– Mortalité (toutes causes, liée au tractus respiratoire
inférieur)
Traitements
• Patients randomisés
– Tiotropium (18 mcg) ou placebo une fois par jour via le
dispositif d’inhalation HandiHaler®
– Permis: Tous les traitements à visée respiratoire pendant
l’étude sauf les anticholinergiques inhalés
• Les patients ont reçu en ouvert de l’ipratropium à
utiliser pendant les 30 jours de la période de suivi
Baseline Characteristics
Characteristic
Tiotropium
Control
(n = 2986)
(n = 3006)
Male (%)
75
74
Age (yrs)*
65 ± 8
65 ± 9
Body Mass Index*
26 ± 5
26 ± 5
29
30
49 ± 28
48 ± 28
46 / 44 / 8
45 / 44 / 9
46 ± 17
46 ± 17
Smoking status
Current smoker (%)
Smoking history (pack-yrs)*
GOLD stage (II / III / IV) (%)
SGRQ total score (units)*
*Mean ± SD
Baseline Spirometry
Pre-Bronchodilator
FEV1 (L)
FEV1 (% predicted)
FVC (L)
FEV1/FVC
SVC
Mean ± SD
Post-Bronchodilator
Tiotropium
Control
Tiotropium
Control
(n = 2986)
(n = 3006)
(n = 2986)
(n = 3006)
1.10 ± 0.40
1.09 ± 0.40
1.33 ± 0.44
1.32 ± 0.44
40 ± 12
39 ± 12
48 ± 13
47 ± 13
2.63 ± 0.81
2.63 ± 0.83
3.09 ± 0.86
3.09 ± 0.90
42 ± 11
42 ± 11
44 ± 11
43 ± 11
2.80 ± 0.82
2.80 ± 0.83
3.21 ± 0.88
3.20 ± 0.90
Baseline and On Treatment+ Respiratory
Medications
Tiotropium
(n = 2986)
Medication (% of patients)
Control
(n = 3006)
Baseline
Baseline
Any respiratory medication
93
93
Short-acting anticholinergic
45
44
Short-acting beta-agonist
69
68
Long-acting beta-agonist*
60
60
Inhaled steroid*
62
62
Theophylline
23
23
Systemic steroids
8
8
Mucolytics
7
7
Leukotriene receptor antagonists
3
3
Supplemental O2
2
2
*Used alone or in combination
Baseline and On Treatment+ Respiratory
Medications
Tiotropium
(n = 2986)
Medication (% of patients)
Baseline
Control
(n = 3006)
On Treatment + Baseline On Treatment +
Any respiratory medication
93
96
93
94
Short-acting anticholinergic
45
17
44
17
Short-acting beta-agonist
69
81
68
79
Long-acting beta-agonist*
60
72
60
72
Inhaled steroid*
62
74
62
74
Theophylline
23
35
23
35
Systemic steroids
8
53
8
55
Mucolytics
7
27
7
27
Leukotriene receptor antagonists
3
5
3
5
Supplemental O2
2
12
2
12
*Used alone or in combination
+ At any time during treatment
including short-term treatment of exacerbations
UPLIFT
Fonction respiratoire
Pre- and Post-bronchodilator FEV1
Mean values at each time point
1.50
Tiotropium
Control
FEV1 (L)
1.40
1.30
*
*
*
1.20
*
*
*
*
*
1.10
*
(n=2494)
Pre-Bronch FEV1
(n=2363)  = 87 – 103 mL
1.00
0
01
Day 30
(steady state)
6
12
18
24
30
36
42
48
Month
*P<0.0001 vs. control. Repeated measure ANOVA was used to estimate means. Means are adjusted for baseline measurements.
Baseline trough FEV1 (observed mean) = 1.116 (trough), 1.347 (peak). Patients with ≥3 acceptable PFTs after day 30 were included in the analysis.
Pre- and Post-bronchodilator FEV1
Mean values at each time point
1.50
Tiotropium
*
*
FEV1 (L)
1.40
*
*
*
*
Control
*
1.30
*
*
1.20
*
*
*
* (n=2516)
Post-Bronch FEV1
*
(n=2374)  = 47 – 65 mL
*
*
*
1.10
*
(n=2494)
(n=2363)
1.00
Pre-Bronch FEV1
 = 87 – 103 mL
0
01
Day 30
(steady state)
6
12
18
24
30
36
42
48
Month
*P<0.0001 vs. control. Repeated measure ANOVA was used to estimate means. Means are adjusted for baseline measurements.
Baseline trough FEV1 (observed mean) = 1.116 (trough), 1.347 (peak). Patients with ≥3 acceptable PFTs after day 30 were included in the analysis.
Rate of Decline in FEV1
Mean slope from day 30 until completion of double-blind treatment
– treated set with ≥3 post-randomization measurements
Tiotropium (mL/yr)
Control (mL/yr)
∆ Tio - Con
95% CI
P-value*
n
Mean (SE)
n
Mean (SE)
Mean (SE)
Pre-bronch
2557
30 (1)
2413
30 (1)
0 (2)
-4, 4
0.95
Post-bronch
2554
40 (1)
2410
42 (1)
2 (2)
-6, 2
0.20
∆ Tio - Con
95% CI
P-value
– treated set with ≥1 post-randomization measurement
Tiotropium (mL/yr)
Control (mL/yr)
n
Mean (SE)
n
Mean (SE)
Mean (SE)
Pre-bronch
2906
29 (1)
2863
29 (1)
0 (2)
-4, 4
0.98
Post-bronch
2904
39 (1)
2851
41 (1)
2 (2)
-6, 2
0.24
*Unadjusted p-value
Annual Decline in Post-Bronchodilator
FEV1 in Major Long-Term COPD Trials
Baseline
FEV1 %
predicted
Study drug
100%
~ 79%
ISOLDE (3 years)
36 – 39%
LHS II (3.3 years)
Study (Duration)
(order: year of
publication)
Current
smokers
Annual decline in FEV1
(mL/year)
Study drug
Placebo
only
Placebo*+
Budesonide
57
69
-
~ 50%
Fluticasone
50
59
-
90%
~ 68%
Triamcinolone
44
47
-
41- 51%
~ 57%
NAC
54
47
-
43%
~ 48%
S/F/SFC
42/42/39
55
-
UPLIFT (3 years)
30%
~ 47%
Tiotropium
37
-
42
UPLIFT (4 years)
30%
~ 47%
Tiotropium
40
-
42
EUROSCOP (3 years)
BRONCUS (3 years)
TORCH (3 years)
post hoc analysis
* All respiratory medications permitted throughout the trial, other than inhaled anticholinergics
Rate of Decline in FEV1
No Baseline LABA or ICS
Mean slope from day 30 until completion of double-blind treatment
– treated set with ≥3 post-randomization measurements
Tiotropium (mL/yr)
Control (mL/yr)
P-value
n
Mean (SE)
n
Mean (SE)
Pre-bronch
789
33 (2)
767
38 (3)
0.085
Post-bronch
787
40 (3)
764
47 (3)
0.048
Model of Slopes According to
Time On or Off ICS/LABA
Pre-bronchodilator FEV1
ON (mL/yr)
OFF (mL/yr)
Tiotropium (n=2561)
29 (2)
33 (3)
Control (n=2422)
28 (2)
39 (3)
P-value
0.52
0.13
ON (mL/yr)
OFF (mL/yr)
Tiotropium (n=2557)
40 (2)
39 (3)
Control (n=2417)
40 (2)
49 (3)
P-value
0.93
0.008
Post-bronchodilator FEV1
Advantage: Use all data points, results interpretable, off ICS/LABA patients
comparable to TORCH
UPLIFT
SGRQ
SGRQ Total Score
SGRQ Total Score (Units)
Improvement
Mean values at each time point
50
Tiotropium (n = 2478)
Control (n = 2337)
SGRQ Total
Score
 = 2.3 – 3.3 units
45
40
*
*
6
12
*
*
*
*
30
36
*
*
35
0
0
18
24
42
48
Month
*P<0.0001 vs. control. Repeated measure ANOVA was used to estimate means. Means are adjusted for baseline measurements. Baseline
SGRQ Total Score (observed mean) = 45.028. Patients with ≥2 acceptable SGRQ Total Scores after month 6 were included in the analysis.
Percentage of Patients With 4-Unit
Improvement in SGRQ Total Score*
50
49.1
47.5
48
46.1
44.9
46
Patients (%)
44
42
41.2
Tiotropium
Control
39.1
40
38
36.5
36.2
3 years
4 years
36
34
32
30
1 year
2 years
All p-values <0.001; *compared to Day 1
UPLIFT
Exacerbations
Exacerbations
1
Tiotropium
n = 2986
Mean (SE)
Control
n = 3006
Mean (SE)
Rate
Ratio
95% CI
P-value
# exacerbations per
patient-year1
0.73 (0.02)
0.85 (0.02)
0.86
0.81, 0.91
<0.001
# exacerbation days
per patient-year1
12.1 (0.32)
13.6 (0.35)
0.89
0.83, 0.95
<0.001
Rate ratio from Poisson regression corrected for treatment exposure and overdispersion
Randomized patients with ≥1 dose of study medication were included in the analysis.
Probability of COPD Exacerbation Leading to
Hospitalization
Probability of exacerbation leading
to hospitalization (%)
Tiotropium
Control
40
30
Hazard ratio = 0.86,
(95% CI, 0.78, 0.95)
20
p=0.002 (log-rank test)
10
0
0
6
12
18
24
Month
30
36
42
48
UPLIFT
Safety
Mortality
Tiotropium
Control
n (%)
n (%)
On-Treatment
381 (12.8)
411 (13.7)
Vital Status (day 1440)
430 (14.4)
Vital Status (day 1470)
446 (14.9)
∆Rates
Hazard Ratio
Tiotropium vs. Control
HR
95% CI
P-value
0.9%
0.84
0.73, 0.97
0.016
491 (16.3)
1.9%
0.87
0.76, 0.99
0.034
495 (16.5)
1.6%
0.89
0.79, 1.02
0.086
Mortality
Tiotropium
Control
n (%)
n (%)
On-Treatment
381 (12.8)
411 (13.7)
Vital Status (day 1440)
430 (14.4)
Vital Status (day 1470)
TORCH
TORCH
∆Rates
Hazard Ratio
Tiotropium vs. Control
HR
95% CI
P-value
0.9%
0.84
0.73, 0.97
0.016
491 (16.3)
1.9%
0.87
0.76, 0.99
0.034
446 (14.9)
495 (16.5)
1.6%
0.89
0.79, 1.02
0.086
193 (12.6)
205 (13.5)
0.9%
0.93
0.77, 1.13
0.48
SFC
Salmeterol
193 (12.6)
231 (15.2)
0.68, 1.02
0.052
SFC
Placebo
SFC vs Sal
2.6%
0.83
SFC vs Pla
(adjusted)
SAE Incidence (per 100 pt-yrs) Reported By >1% in
Any Treatment Group**
Tiotropium
n=2986
Control
n=3006
Rate Ratio
(Tio/Con)
95% CI
3.56
4.21
0.84
0.73, 0.98*
Angina
0.51
0.36
1.44
0.91, 2.26
Atrial fibrillation
0.74
0.77
0.95
0.68, 1.33
Cardiac failure
0.61
0.48
1.25
0.84, 1.87
Cardiac failure congestive
0.29
0.48
0.59
0.37, 0.96*
Coronary artery disease
0.21
0.37
0.58
0.33, 1.01
Myocardial infarction
0.69
0.97
0.71
0.52, 0.99*
11.32
13.47
0.84
0.77, 0.92*
Bronchitis
0.37
0.31
1.20
0.73, 1.98
COPD exacerbation
8.19
9.70
0.84
0.76, 0.94*
Dyspnea
0.38
0.62
0.61
0.40, 0.94*
Pneumonia
3.28
3.46
0.95
0.81, 1.11
Respiratory failure
0.90
1.31
0.69
0.52, 0.92*
Cardiac SOC
Respiratory (lower) SOC
*p<0.05; **excluding lung cancer (multiple different terms)
UPLIFT
Conclusions
Summary - Efficacy
Primary Endpoint
– No effect on rate of decline of pre/post-bronchodilator FEV1
• Subgroup difference in group not receiving LABA or ICS
Secondary Endpoints
– Improvement in FEV1, FVC and SVC maintained throughout
• No effect on rate of decline of FVC and SVC.
– Improvement in SGRQ maintained throughout study
• Tiotropium group did not cross baseline after 4 years treatment
– Reduction in risk for exacerbation/hospitalization
Summary - Safety
•Reduced mortality
•Evidence for reduced cardiovascular morbidity,
including myocardial infarction
– No increased risk for stroke
•Reduced lower respiratory morbidity
– Decreased risk for respiratory failure
Overall Conclusions
•Although UPLIFT did not demonstrate changes in the
rate of decline in lung function over 4 years with
tiotropium in the setting of concomitant respiratory
medications, it did reveal other benefits of
tiotropium:
– maintenance of improved lung function and HRQoL over 4
years
– reduced risk of exacerbations & exacerbation-related
hospitalizations
– reduced respiratory morbidity and cardiac morbidity and
improved overall survival