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COPD The Silent Killer

Chronic Respiratory Disease is a Leading Cause of Chronic Disease Deaths Worldwide

The World Health Organization (WHO) projected that, in 2005, chronic respiratory disease would be the third-leading cause of deaths from chronic disease worldwide
Adapted from: World Health Organization. Preventing chronic diseases: a vital investment. (2005) Available at: http://www.who.int/chp/chronic_disease_report/contents/en/index.html (accessed June 2009).

Change in Death Rates for Cardiovascular and Pulmonary Disease

Pauwels RA, Rabe KF. Lancet. 2004; 364: 613-620

Prevalence COPD in Asia-Pacific Region

Tan and NG Chest 2008; 133:517

Definition

COPD, a common preventable and treatable disease, is characterized by persistent airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response in the airways and the lung to noxious particles or gases
REVISED 2011

Exacerbations and comorbidities contribute to the overall severity in individual patients

GOLD. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease. Revised 2011. Available from: http://www.goldcopd.org

General considerations for FEV1 decline


Annual
FEV1 decline in healthy subjects
FEV1 decline in COPD patients normal decline

FEV1 decline (mL)

Potential Room for Improvement

additional decline

1. Celli BR, MacNee W. Eur Respir J. 2004; 23: 932946; 2. GOLD. Global Initiative for Chronic Obstructive Lung Disease. Updated 2010. Available: www.goldcopd.com

Mechanisms of Airflow Limitation in COPD (Peripheral Airways)

Adapted from: Barnes P. NEJM 2000; 343; 269

FEV1 decline in COPD: Potentially reversible mechanisms


Smooth muscle contraction Mucus hypersecretion

Cholinergic tone

Loss of alveolar attachment Peribronchial fibrosis


1. Celli BR, et al. Am J Respir Crit Care Med 2008; 178: 33238; 2. Beaucage F, Decramer M, et al. Am J Respir Crit Care Med .2008; 177: A401.

Pathophysiology of COPD: Vagal Nerve System


Central nervous system Vagus nerve
ACh
Parasympathetic ganglion

Airway smooth muscle constriction

Inflammatory cell mediators

ACh

Cholinergic receptors

ACh

Submucosal gland

Airway epithelium

Irritants (e.g. cigarette smoke, bacteria, viruses)

Mucus Hypersecretion

Adapted from: Hansel T/Barnes P. An Atlas of COPD. 2004

Cholinergic Receptor Subtypes in Airways


Pre-ganglionic nerve Nicotinic receptors (+) Parasympathetic ganglion M1 receptors (+)

Post-ganglionic nerve

Ideal anti cholinergic


M2 receptors ()

ACh Airway smooth muscle

M3 receptors (+)

Hansel T / Barnes P. An Atlas of COPD. 2004

FEV1 Model of Disease Progression in COPD


100%

COPD Stages

FEV1 (% of value at age 25)

75%

Diagnosis
Moderate

50%

Treatment
Severe

25%

Very Severe
0% 25 50 Age (years)

75

Adapted from Fletcher C and Peto R, BMJ 1977; 1:1645-1648. Imagery courtesy ODonnell D

The Progression of COPD


Mild COPD Severe COPD

What can we do ???

Key Indicators for Considering a Diagnosis of COPD

Buku Lengkap Diagnosis dan Penatalaksanaan PPOK PDPI, Juli 2011

Stable COPD Treatment Goals

Buku Lengkap Diagnosis dan Penatalaksanaan PPOK PDPI, Juli 2011

UPLIFT : FEV1 Over 4-Year Trial Duration


Asian cohort1 Japanese cohort1
rate of decline: 11 mL/yr pre-BD (P=0.24) 13 mL/yr post-BD (P=0.16)
Tiotropium Control

rate of decline: -2 mL/yr pre-BD (P=0.83) 5 mL/yr post-BD (P=0.54)


1.50 1.40 1.30 FEV1 (L) 1.20 1.10 1.00 0.90 0.80 0.00 01 6 12 18 24 30 36 42 48 Month

Significant lung function improvement with tiotropium in total, Asian and Japanese cohort
Tiotropium
Control 1.50 1.40 1.30 1.20 1.50 1.40 1.30 Tiotropium Control

rate of decline: 0 mL/yr pre-BD (P=0.95) 2 mL/yr post-BD (P=0.21)

Total cohort2

* *

* *

* *

*
*

* *

* *

* *

* * * * *

* *

* *

1.10

* *

* *

* *

* *

* *

* *

* *

* *

Post-BD

Post-BD * Tiotropium (n=46) Control (n=43) Pre-BD * Tiotropium (n=45) Control (n=43)

1.20 1.10 1.00 0.90 0.80 0.00

* *

* Control (n=2374)
Pre-BD

Post-BD Tiotropium (n=2516)

* Tiotropium (n=2494)
Control (n=2363)

* Tiotropium (n=156)
Control (n=147) Tiotropium (n=152) Control (n=145)

1.00 0.90 0.80 0.00

* * Pre-BD

01 6 12 18 24 30 36 42 48 Day 30 Month

01 6 12 18 24 30 36 42 48 Day 30 Month

Day 30

*P<0.05 vs control. Difference, tiotropium control. BD, bronchodilator.


1Fukuchi

Y, et al. Respirology 2011; 16: 825-835; 2Adapted from Tashkin DP, et al. N Engl J Med 2008;359:1543-1554.

UPLIFT : SGRQ Total Score


Asian Cohort1
= 1.5-6.1 units
Tiotropium (n=184) Control (n=178)

Japanese Cohort1
= 1.1-6.2 units
Tiotropium (n=48) Control (n=43)

Total Cohort2
= 2.3-3.3 units
Tiotropium (n=2478) Control (n=2337)

Improvement

SGRQ Total Score (Units)

Significant SGRQ improvement with tiotropium in total, Asian and Japanese cohort
50

50

50

45

45

45

40

40

40

35

* * * *
0 6 12 18 24 30 36 42 48

35

*
0 6

* *
35

* * * * * * * *
0 6 12 18 24 30 36 42 48

12 18 24 30 36 42 48

Month

Month

Month

*P<0.05 vs. control. Repeated measure ANOVA was used to estimate means. Estimated means are adjusted for baseline measurements. Patients with 2 acceptable SGRQ Total Scores after Month 6 were included in the analysis.
1Fukuchi

Y, et al. Respirology 2011; 16: 825-835; 2Adapted from Tashkin DP, et al. N Engl J Med 2008;359:1543-1554.

The UPLIFT Lesson


Similar to the overall cohort, 4 years treatment with tiotropium provided the following benefits in the subgroup of COPD patients from Asia (Improved lung function, Improved HRQoL, Reduced exacerbations) These data indicate that tiotropium may be used in patients from Asia in accordance with current international treatment guidelines Tiotropium is beneficial to COPD patients of various severities (GOLD stages II to IV) and has clearly demonstrated benefit to GOLD stage II patients

1Fukuchi

Y, et al. Respirology 2011; 16: 825-835

The Clinical Course of COPD: Consequences of Exacerbations


Reduced health-related quality of life Accelerated decline in FEV1

Exacerbations

Increased mortality with exacerbation hospitalizations

Increased health resource utilization and direct costs

Systemic inflammation increases during ECOPD potential mechanism to explain the increased risk of vascular events Plasma levels of the cardiac biomarkers NT-proBNP and troponin T were abnormal in a significant number of ECOPD patients hospitalized both markers predicted mortality

Patients with COPD had increased circulating platelete-monocyte aggregates further increased during ECOPD
Fabbri LM, et al. Thorax. 2011; 66(9): 745-747

POET-COPD: Tiotropium Significantly Delayed Time to First Exacerbation


50 Probability of COPD exacerbation (%) 45 Tiotropium Salmeterol

40
35 30 25 20 15 10 5 0 0 30 60 90 120 150 180 210 240 270 300 330 360 Time to event (days)

17% Risk difference

Hazard ratio = 0.83* (95% CI, 0.77, 0.90) P<0.001 (log-rank test)

No. of patients at risk: Tiotropium Salmeterol 3707 3369 3136 2955 2787 2647 2561 2455 2343 2242 2169 2107 1869 3669 3328 3028 2802 2605 2457 2351 2251 2137 2050 1982 1915 1657 Vogelmeier C et al. N Engl J Med 2011;364:1093-1103.

*Cox regression adjusted for (pooled) centre and treatment.

POET-COPD: Tiotropium Significantly Delayed Time to First Severe Exacerbation


20 Probability of hospitalized COPD exacerbation (%)

Tiotropium Salmeterol
15

10

28% Risk difference


Hazard ratio = 0.72* (95% CI, 0.61, 0.85) P<0.001 (log-rank test)

0 30 60 90 120 150 180 210 240 270 300 330 360 Time to event (days) No. of patients at risk:
Tiotropium Salmeterol 3707 3564 3453 3359 3285 3217 3177 3125 3066 3017 2977 2984 2663 3669 3502 3362 3244 3172 3080 3032 2982 2921 2870 2834 2806 2489 Vogelmeier C et al. N Engl J Med 2011;364:1093-1103.

*Cox regression adjusted for (pooled) centre and treatment.

Tiotropium Reduced Number of Exacerbations


RR 0.89*

Adjusted yearly rate

1 (95% CI 0.83, 0.96) RR 0.93* P=0.002 0.9 (95% CI 0.86, 1.00) P=0.048 0.8
0.72

Tiotropium Salmeterol

0.7 0.6 0.5 0.4 0.3 0.2 0.1 0

0.64 0.59 0.54


RR 0.73*

(95% CI 0.66, 0.82) P<0.001


0.13

0.09

All exacerbations

Moderate exacerbations

Severe exacerbations

RR=rate ratio. *Poisson regression correcting for overdispersion and adjusted for treatment exposure. Vogelmeier C et al. N Engl J Med 2011;364:1093-1103.

POET-COPD: Time to First Exacerbation by Subgroup Consistent with Overall Cohort


Characteristic
Age group <55 y 55 to <65 y 65 y Sex Male Female GOLD stage Stage II Stage III Stage IV

Tiotropium Salmeterol Hazard Ratio P-value* n/N n/N (95% CI)


0.76
237/655 484/1462 556/1590 913/2759 364/948 258/665 522/1426 634/1578 1016/2747 398/922 0.88 (0.74, 1.05) 0.87 (0.77, 0.98) 0.83 (0.74, 0.93)

Hazard ratio for at least one COPD exacerbation

0.83
0.86 (0.78, 0.94) 0.84 (0.73, 0.97)

Tiotropium was significantly more effective across 0.05 635/1833 0.88 (0.79, 0.99) 561/1781 almost all subgroup 589/1597 627/1545 0.86 (0.77, 0.97)compared to salmeterol
127/329 152/291 746/1896 668/1773 134/271 501/1254 468/1284 311/860 839/1955 575/1714 0.64 (0.50, 0.81) 0.64 0.84 (0.75, 0.93) 0.87 (0.78, 0.97) 0.66 (0.51, 0.85) 0.89 (0.79, 1.02) 0.87 (0.76, 0.99) 0.85 (0.72, 1.00) 0.87 (0.79, 0.96) 0.82 (0.73, 0.92) 0.17

Smoking status Noncurrent 678/1929 Current 599/1778 BMI group <20 20 to <25 25 to <30 30 105/286 455/1230 424/1276 293/915

ICS use at baseline 785/1986 Yes No 492/1721

0.41

*n=no. patients with event; N=total no. patients. 0.4 0.6 *Subgroup by treatment interaction. GOLD=Global Initiative for Chronic Obstructive Lung Disease; BMI=body-mass index; ICS=inhaled corticosteroid.

0.8 1 1.2 1.4 Favours tiotropium Favours salmeterol

Vogelmeier C et al. N Engl J Med 2011;364:1093-1103.

POET-COPD: Discontinuing ICS did not Increase Rate of Exacerbations*


Tiotropium n Exacerbation rate (95% CI) 0.78 (0.73, 0.85) 0.67 (0.57, 0.79) n Salmeterol Exacerbation rate (95% CI) 0.81 (0.75, 0.88) 0.86 (0.74, 0.99)

Continued ICS during trial Discontinued ICS during trial

1452

1401

395

416

*Analysis in subset of patients who were receiving ICS at baseline. ICS=inhaled corticosteroid.
Vogelmeier C et al. N Engl J Med 2011;364:1093-1103.

POET-COPD: More Patients Receiving Concomitant ICS Experienced Pneumonia


180 reported pneumonia cases
158 (87.8%) radiologically confirmed
70 in the tiotropium group 88 in the salmeterol group

Higher numbers of patients with 1 radiologically

confirmed pneumonia were receiving concomitant ICS


for 1 day on treatment
n=89, 2.7% (n=72 hospitalized) concomitant ICS

n=59, 1.5% (n=46 hospitalized) no concomitant ICS


Vogelmeier C et al. N Engl J Med 2011;364:1093-1103.

The POET-COPD Lesson


Tiotropium was significantly more effective than salmeterol in almost all assessed exacerbation endpoints and across all major patient subgroups Addition of ICS did not affect the outcome of exacerbation; prevention of exacerbations by tiotropium alone appears to be efficient Adverse events seen in the POET-COPD trial were consistent with the well-established, long-term safety profile of tiotropium

Stable COPD Treatment Goals

UPLIFT 4 years study


UPLIFT 4 years study UPLIFT 4 years study and POET-COPD 1 year study

Buku Lengkap Diagnosis dan Penatalaksanaan PPOK PDPI, Juli 2011

Management of COPD in Indonesia


Berotec Combivent UDV

Spiriva early treatment start from stage II COPD

Buku Lengkap Diagnosis dan Penatalaksanaan PPOK PDPI, Juli 2011

Take Home Messages


Cholinergic tone is the basic of COPD patophysiology Early intervention impact disease progression The UPLIFT and POET COPD trials of support initiating tiotropium (Spiriva) as the preferred foundation maintenance therapy as it improves lung function, improves quality of life as well as reduces the risk of COPD exacerbations In case of exacerbations, fenoterol (Berotec) or combination of ipratropium/salbutamol (Combivent UDV) can be used as reliever in every stage of COPD

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