Early diagnosis and treatment of COPD Marc Decramer Chief Respiratory Division KU Leuven President ERS
ALAT 2010
Campus Gasthuisberg KU Leuven
Hospital
Research & Education
Questions • • • • •
Is it a problem? What is early COPD? How do we diagnose COPD? Is early diagnosis important? Is early treatment important?
Is it a problem?
th
Ph Afr ili ica pp in Tu es rk Po ey la nd US No A rw Au ay s Ur tria ag ua Ch y Ca ina n Au ada st G rali er a m an Ic y Ve ela ne n d zu el a Ch il Br e a M zil ex ic o
So u
Prevalence of GOLD II+ COPD Prevalence per 100 25
Men Women
20
15
10
5
0
Mannino and Buist, Lancet 2007; 370: 765–773.
COPD in Belgium Total
682,332
I
259,286
II
272,932
III+IV
150,113
Lundb채ck et al. Respir Med 2003, 97: 115-122. Zielinski et al. Chest 2001, 119: 731-736.
What is early COPD?
COPD (n=79)
GOLD III 10.1 %
GOLD II 49.4%
GOLD IV 1.3%
GOLD I 39.2%
Characteristics according to GOLD stages Variable
GOLD I
GOLD II
GOLD III
GOLD IV
P
Age yrs
66
66
64
63
0.48
FEV1 % pred
85
65
40
25
<0.0001
SGRQ total
27
36
51
64
<0.0001
Exacerbation
2.0
1.0
2.0
2.0
<0.0001
Comorbidities %
86
88
84
59
NA
Burgel et al. Eur Respir J 2010; in press.
Characteristics according to 4 new phenotypes Variable
Old mild Y moderate Old severe
Y severe
Age yrs
68
59
73**
58
FEV1 % pred
68
46
43**
31
MMRC
1.0
1.0
3.0**
3.0
Exacerbation
0.0
1.0
2.0
4.0
Comorbidities %
107
44
124
38
** p<0.05 compared with phenotype 4
Burgel et al. Eur Respir J 2010; in press.
How do we diagnose COPD?
Diagnostic value of the questionnaire Obstructive
Normal
Total
Symptoms+
126 (18%)
577 (82%)
703
Symptoms-
90 (4%)
2,130 (96%)
2,220
Total
216 (7%)
2,707 (93%)
2,923
Buffels et al. Chest 2004; 125: 1394-1399.
Perceived Severity of Respiratory Condition by Degree of Breathlessness (MRC Scale) % 100 11% 17% Mild +Moderate
80 60 40 79%
90%
87%
77%
61%
42%
One
Two
Three
Four
Five
20 0 All Patients
MRC Degree of Breathlessness: Least
Most
P4. Overall, how severe is your (CONDITION), now? Is it severe, moderate or mild?
Rennard, Decramer et al. Eur Respir J 2002; 20: 799-805.
n=3,265
Is early diagnosis important?
Mortality in NHANES I 1.0 0.8
No lung disease Symptoms only
0.6
COPD GOLD I Restrictive disease COPD GOLD II
0.4 0.2
COPD III+IV
0.0 0
5
10
15
20
Follow-up (years)
Mannino et al. Thorax 2003; 58: 388-393.
Is early treatment important?
COPD: a progressive lung disease
FEV1 (% pred.)
85 80
Sustained Quitters 27 ml/year
75 70 Continuing Smokers 60 ml/year
65 60 0
2
4
6
8
10
Years follow-up Anthonisen et al. Am J Resp Crit Care Med 2002; 66: 675-9.
Is active detection of COPD required? â&#x20AC;˘ No irrefutable evidence that active detection and early treatment of COPD is required. â&#x20AC;˘ Accumulating circumstantial evidence that early treatment is useful.
Questions 1. Can we improve patients in early stages with pharmacotherapy? 2. Can we modify the course of the disease in these patients?
UPLIFT
GOLD stage II
Decramer et al. Lancet 2009; 374:1171-1178.
GOLD Stage II Lung Function 1.80
Tiotropium
*
*
*
*
FEV1 (L)
1.60
*
*
*
1.40
*
*
*
*
*
Control
*
*
*
* Post-Bronch FEV1
*
*
∆ = 52 – 82 mL
Pre-Bronch FEV1
1.20
∆ = 100 – 119 mL
0 01 Day 30 (steady state)
6
12
18
24
30
36
42
48
Month
Decramer et al. Lancet 2009; 374: 1171-1178. *P<0.0001 vs. control. Repeated measure ANOVA was used to estimate means. Estimated means are adjusted for baseline measurements. Month 0 values are observed means. Patients with ≥3 acceptable PFTs after day 30 were included in the analysis. Tiotropium: Month 0 n = 1196, Month 48 n = 923; Control: Month 0 n = 1140, Month 48 n = 853
Rate of Decline in FEV1 GOLD Stage Post-bronchodilator FEV1 GOLD Stage
Tiotropium (mL/yr)
Control (mL/yr)
â&#x2C6;&#x2020; Tio - Con
P-value
n
Mean (SE)
n
Mean (SE)
Mean (SE)
II
1218
43 (2)
1158
49 (2)
6 (3)
0.02
III
1104
39 (2)
1031
38 (2)
0 (3)
0.87
IV
194
32 (5)
185
23 (5)
-9 (7)
0.24
P-value for subgroup by treatment interaction = 0.07 Decramer et al. Lancet 2009; 374:1171-1178.
Exacerbations: GOLD Stage II
Ratio (95% CI)
P-value
Tiotropium
Control
n = 1384
n = 1355
Time to first exacerbation
23.1 (21.0, 26.3)
17.5 (15.9, 19.7)
0.82 (0.75, 0.90)*
<0.0001*
# exacerbations/pt yr mean (95% CI)
0.56 (0.52, 0.60)
0.70 (0.65, 0.75)
0.80 (0.72, 0.88)†
<0.0001†
Decramer et al. Lancet 2009; 374: 1171-1178. *Hazard ratio (control vs. tiotropium) and p-value were estimated using Cox regression with treatment, GOLD stage, and treatment by GOLD stage interaction as covariates. † Ratio (tiotropium/control) and p-value were estimated using the Poisson with Pearson overdispersion model adjusting for treatment exposure. Randomized patients taking ≥1 dose of study medication were included in the analysis.
UPLI FT Maintenance
na誰ve
Troosters et al. Eur Respir J 2010; 36:65-73.
Pre- and Post-bronchodilator FEV1 Maintenance naïve Tiotropium
1,60
Control
FEV1 (L)
1,50 1,40
*
*
*
1,30
*
*
*
*
*
*
1,20
Pre-Bronch FEV1 ∆ = 99 – 160 mL
1,10 1,00 0 01
6
Day 30 (steady state)
12
18
24
30
36
42
48
Month
* p< 0.0001
Troosters et al. Eur Respir J 2010; 36:65-73.
Pre- and Post-bronchodilator FEV1 Maintenance naïve 1,60
*
*
*
FEV1 (L)
1,50 1,40
*
*
*
Tiotropium
*
*
1,30
*
*
*
*
Control
*
*
*
*
*
*
1,20
Post-Bronch FEV1 ∆ = 52 – 110 mL
Pre-Bronch FEV1 ∆ = 99 – 160 mL
1,10 1,00 0 01 Day 30 (steady state)
6
12
18
24
30
36
42
48
Month
* p< 0.0001
Troosters et al. Eur Respir J 2010; 36:65-73.
Rate of Decline in FEV1 Maintenance naïve Mean slope from day 30 until completion of double blind treatment for maintenance therapy subgroups – treated set with ≥3 post-randomization measurements Tiotropium (mL/yr)
Control (mL/yr)
P-value
n
Mean (SE)
n
Mean (SE)
Pre-bronch
355
35 (3)
335
45 (4)
0.049
Post-bronch
354
42 (4)
336
53 (4)
0.026
Troosters et al. Eur Respir J 2010; 36:65-73.
SGRQ Total Score Maintenance naïve SGRQ Total Score (Units)
Improvement
50
Tiotropium
Control
45
SGRQ Total Score ∆ = 2.3 – 6.9 units
40
*
35
*
*
6
12
*
*
*
*
*
18
24
30
36
42
30 0 0
48
Month * p< 0.05
Troosters et al. Eur Respir J 2010; 36:65-73.
Decline in SGRQ Total Scores Maintenance naïve Mean slope from month 6 until completion of double blind treatment for maintenance therapy subgroups – treated set with ≥2 post-randomization SGRQ measurements Tiotropium (units/yr)
Total
Control (units/yr)
n
Mean (SE)
n
Mean (SE)
336
0.66 (0.23)
353
1.71 (0.24)
∆ Tio - Pla
P-value
1.05 (0.34)
0.002
Troosters et al. Eur Respir J 2010; 36:65-73.
Effect on FEV1decline
1350
FEV1 (mL)
1300 SFC 39 mL/yr
1250 1200
FP
42 mL/yr
1150
SAL
42 mL/yr
1100
Pla
55 mL/yr
0 No of patients Placebo 1261 SAL 1334 FP 1356 SFC 1392
24
1248 1317 1346 1375
48
72 96 Time ( weeks)
1128 1218 1230 1281
1049 1127 1157 1180
120
979 906 1054 1012 1078 1006 1139 1073
156
819 934 908 975
Celli et al. Am J Respir Crit Care Med 2008; 178: 332-338.
Treatment effects in different GOLD stages Outcome
GOLD II (2,156)
GOLD III (3,019)
GOLD IV (937)
Mortality ↓ %
33
5
30
Exacerbations ↓ %
31
26
14
FEV1 ↑ mL
101
82
96
Decline FEV1 ↓ mL/yr
16
16
11
SGRQ ↓ units
2.3
3.3
5.9
Jenkins et al. Respiratory Research 2009; 10: 59.
Early treatment of COPD in guidelines â&#x20AC;Śconvincing evidence that patients in the early stages of the disease improve considerably with drug treatment. This includes suggestive evidence for disease modification.
What should be in the guidelines?
FP + LHS + UPLIFT + TORCH Fletcher & Peto: Smokers (modified) TORCH® GOLD II: Placebo UPLIFT® GOLD II: Control TORCH GOLD III: Placebo UPLIFT® GOLD III: Control TORCH GOLD IV: Placebo UPLIFT® GOLD IV: Control
TORCH® GOLD II: SFC UPLIFT® GOLD II: Tiotropium TORCH GOLD III: SFC UPLIFT® GOLD III: Tiotropium TORCH GOLD IV: SFC UPLIFT® GOLD IV: Tiotropium
60 50 40
Age (years)
72
70
68
66
64
20 62
det s uj da e gVaErFo % (1
30