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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



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