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Chronic Obstructive Pulmonary Disease (COPD)
โครงการประชุมเชิงปฏิบัติการ งานเภสัชกรรมคลนิิก คร้ังที่ 18/2557 เร่ือง Pharmaceutical Care for Patients with Chronic Diseases
19 June 2014
GOLD, 2014: Definitions
© 2014 Global Initiative for Chronic Obstructive Lung Disease
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.
Exacerbations and comorbidities contribute to the
overall severity in individual patients.
© 2014 Global Initiative for Chronic Obstructive Lung Disease
A disease state characterized by the presence of airflow obstruction due to chronic bronchitis (and)/ or emphysema; the airflow obstruction is generally progressive, may be accompanied by airway hyperreactivity, and may be partially reversible.
Definitions (American Thoracic Society, ATS)
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Asthma and COPD Overlap Syndrome (ACOS)
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5
Pathogenesis of COPD
Noxious particles & gases
Lung inflammation
COPD pathology
Antiproteinases
Proteinases
Anti-oxidants
Oxidative stress
Mechanism underlying airflow limitation in COPD
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Risk factors for COPD Host factors Gene (e.g., alpha-1 antitrypsin deficiency) Airway hyperresponsiveness Lung Growth
Exposures Smoking Occupational dusts and chemicals Air pollution Infections Asthma / bronchial hyperreactivity
Aging Populations
Asthma
Sensitizing agent
COPD
Noxious agent
Asthmatic airway inflammation CD4+ T-lymphocytes
Eosinophils
COPD airway inflammation CD8+ T-lymphocytes
Macrophages
Neutrophils
Airflow limitation Completely
reversible
Completely
irreversible
Small airway disease Airway inflammation
Airway remodeling
Parenchymal destruction Loss of alveolar attachments
Decrease of elastic recoil
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Key indicators for considering a Dx of COPD
A clinical diagnosis of COPD should be considered in any patient who has dyspnea, chronic cough or sputum production, and a history of exposure to risk factors for the disease.
Spirometry is required to make the diagnosis; the presence of a post-bronchodilator FEV1/FVC < 0.70 confirms the presence of persistent airflow limitation and thus of COPD.
Diagnosis of COPD Symptoms of COPD
Dyspnea: Progressive, persistent and worse with exercise.
Chronic cough: May be intermittent and may be unproductive.
Chronic sputum production: COPD patients commonly cough up sputum.
Spirometry: FEV1/FVC ratio < 0.70 PLUS an FEV1 < 80% predicted that is incompletely reversible with inhaled bronchodilator
Absence of an alternative explanation for the symptoms and airflow limitation (Diff Dx)
Assess symptoms Assess degree of airflow limitation using spirometry
Assess risk of exacerbations
Assess comorbidities
COPD Assessment Test (CAT)
or
Clinical COPD Questionnaire (CCQ)
or
mMRC Breathlessness scale
Global Strategy for Diagnosis, Management and Prevention of COPD
Assessment of COPD
© 2014 Global Initiative for Chronic Obstructive Lung Disease
Assess symptoms
COPD Assessment Test (CAT): An 8-item measure of health status impairment in COPD (http://catestonline.org).
Clinical COPD Questionnaire (CCQ): Self-administered questionnaire developed to measure clinical control in patients with COPD (http://www.ccq.nl).
Breathlessness Measurement using the Modified British Medical Research Council (mMRC) Questionnaire: relates well to other measures of health status and predicts future mortality risk.
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mMRC (Modified Medical Research Council Dyspnea Score)
ระดบั 0: ปกติไม่มีเหน่ือยง่าย ระดบั 1: มีอาการเหน่ือยง่ายเม่ือเดินเรว็ ๆ ข้ึนทางชนั ระดบั 2: เดินในพื้นราบไม่ทนัเพื่อนท่ีอยู่ในวยัเดียวกนั เพราะเหน่ือย หรือต้องหยุดเดินเป็นพกัๆ ระดบั 3 : เดินได้น้อยกว่า 100 เมตร ระดบั 4 : เหน่ือยเวลาทาํกิจวตัรประจาํวนั เช่น ใส่เส้ือผ้า อาบน้ําแต่งตวั จนไม่สามารถออกนอกบ้านได้
เกณฑ์การให้คะแนนภาวะหายใจลาํบาก ซ่ึงแบ่งระดบัความรุนแรงของภาวะหายใจลาํบากเป็น 5 ระดบั
CAT (COPD Assessment Test)
การประเมินผลกระทบของ COPD ต่อผู้ป่วย ประกอบด้วยคาํถาม 8 ข้อ ข้อละ 5 คะแนน เต็ม 40 คะแนน คะแนน < 10 แสดงว่ามีผลกระทบน้อย คะแนน > 10 แสดงว่ามีผลกระทบมาก
Assess symptoms
Assess degree of airflow limitation
Use spirometry for grading severity
according to spirometry, using four
grades split at 80%, 50% and 30% of
predicted value
Global Strategy for Diagnosis, Management and Prevention of COPD
Assessment of COPD
© 2014 Global Initiative for Chronic Obstructive Lung Disease
Classification of severity of airflow limitation (based on postbronchodilator FEV1)
In patients with FEV1/FVC <0.70: Stage I: mild FEV1 ≥80% predicted Stage II: moderate 50% ≤FEV1<80% predicted Stage III: severe 30% < FEV1 < 50% predicted Stage IV: very severe FEV1 < 30% predicted
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Assess symptoms
Assess degree of airflow limitation
Assess risk of exacerbations
Use history of exacerbations and spirometry.
• > 2 exacerbations within the last year
• or an FEV1 < 50 % of predicted value
are indicators of high risk.
• > 1 hospitalization for a COPD exacerbation – high risk
Global Strategy for Diagnosis, Management and Prevention of COPD
Assessment of COPD
© 2014 Global Initiative for Chronic Obstructive Lung Disease
Global Strategy for Diagnosis, Management and Prevention of COPD
Combined Assessment of COPD
© 2014 Global Initiative for Chronic Obstructive Lung Disease R
isk
(G
OLD
Cla
ssif
icat
ion
of
Air
flo
w L
imit
atio
n))
Ris
k
(Exa
cerb
atio
n h
isto
ry)
≥ 2 or > 1 leading to hospital admission
1 (not leading to hospital)
admission) 0
Symptoms
(C) (D)
(A) (B)
CAT < 10
4
3
2
1
CAT > 10
Breathlessness mMRC 0–1 mMRC > 2
Global Strategy for Diagnosis, Management and Prevention of COPD
Combined Assessment of COPD
© 2014 Global Initiative for Chronic Obstructive Lung Disease
If CAT < 10 or mMRC 0-1:
Less Symptoms/breathlessness (A or C)
If CAT > 10 or mMRC > 2:
More Symptoms/breathlessness (B or D)
C D
A B
CAT<10 CAT >10
mMRC 0-1 mMRC >2
ASSESS Symptom first
Global Strategy for Diagnosis, Management and Prevention of COPD
Combined Assessment of COPD
© 2014 Global Initiative for Chronic Obstructive Lung Disease
If GOLD 3 or 4 or ≥ 2 exacerbations per year or > 1 leading to hospital admission:
High Risk (C or D) If GOLD 1 or 2 and only 0 or 1 exacerbations per year (not leading to hospital admission): Low Risk (A or B)
C D
A B
Assess risk of exacerbations next
4
3
2
1
>2
1
0
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Global Strategy for Diagnosis, Management and Prevention of COPD
Combined Assessment of COPD
© 2014 Global Initiative for Chronic Obstructive Lung Disease
C D
A B
4
3
2
1
>2
1
0
Patient Characteristic Spirometric
Classification
Exacerbations
per year
CAT mMRC
A Low Risk
Less Symptoms GOLD 1-2 ≤ 1 < 10 0-1
B Low Risk
More Symptoms GOLD 1-2 ≤ 1 > 10 > 2
C High Risk
Less Symptoms GOLD 3-4 > 2 < 10 0-1
D High Risk
More Symptoms GOLD 3-4 > 2 > 10
> 2
CAT<10 CAT >10
mMRC 0-1 mMRC >2
Global Strategy for Diagnosis, Management and Prevention of COPD
Assess COPD Comorbidities
COPD patients are at increased risk for:
• Cardiovascular diseases • Osteoporosis
• Respiratory infections • Anxiety and Depression • Diabetes • Lung cancer • Bronchiectasis
These comorbid conditions may influence mortality and
hospitalizations and should be looked for routinely, and
treated appropriately.
© 2014 Global Initiative for Chronic Obstructive Lung Disease
Global Strategy for Diagnosis, Management and Prevention of COPD
Differential Diagnosis:
COPD and Asthma
COPD
• Onset in mid-life
• Symptoms slowly progressive
• Long smoking history
ASTHMA
• Onset early in life (often childhood)
• Symptoms vary from day to day
• Symptoms worse at night/early morning
• Allergy, rhinitis, and/or eczema also present
• Family history of asthma
© 2014 Global Initiative for Chronic Obstructive Lung Disease
Global Strategy for Diagnosis, Management and Prevention of COPD
Therapeutic Options: Key Points
Smoking cessation has the greatest capacity to influence the natural history of COPD. Health care providers should encourage
all patients who smoke to quit.
All COPD patients benefit from regular physical activity and should repeatedly be encouraged to
remain active.
© 2014 Global Initiative for Chronic Obstructive Lung Disease
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Appropriate pharmacologic therapy can
reduce COPD symptoms
reduce the frequency and severity of exacerbations
improve health status and exercise tolerance.
None of the existing medications for COPD has been shown conclusively to modify the long-term decline in lung function.
Global Strategy for Diagnosis, Management and Prevention of COPD
Therapeutic Options: Key Points
© 2014 Global Initiative for Chronic Obstructive Lung Disease
Beta2-agonists
Short-acting beta2-agonists (SABA): salbutamol
Long-acting beta2-agonists (LABA): salmeterol, formoterol, indacaterol
Anticholinergics (anti-muscarinic agents)
Short-acting anticholinergics (SAMA): ipratropium
Long-acting anticholinergics (LAMA): tiotropium
Combination SABA + SAMA in one inhaler
Combination LABA + LAMA in one inhaler
Methylxanthines: theophylline SR
Inhaled corticosteroids (ICS)
Combination LABA + ICS in one inhaler
Systemic corticosteroids
Phosphodiesterase-4 inhibitors: roflumilast
© 2014 Global Initiative for Chronic Obstructive Lung Disease
Bronchodilator medications are central to the symptomatic
management of COPD.
Bronchodilators are prescribed on an as-needed or on a regular basis to prevent or reduce symptoms.
The principal bronchodilator treatments are beta2-agonists, anticholinergics, theophylline or combination therapy.
The choice of treatment depends on the availability of
medications and each patient’s individual response in
terms of symptom relief and side effects..
Pharmacotherapy: Bronchodilators
Long-acting inhaled bronchodilators are convenient and more
effective for symptom relief than short-acting bronchodilators.
Long-acting inhaled bronchodilators
reduce exacerbations and related hospitalizations
improve symptoms and health status.
Combining bronchodilators of different pharmacological classes may improve efficacy and decrease the risk of side effects compared to increasing the dose of a single bronchodilator.
Pharmacotherapy: Bronchodilators
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Bronchodilators: Theophylline
Mode of action: smooth muscle relaxation due to phosphodiesterase inhibition (PDE-IV), increases diaphragmatic contractility, may reduce inflammation
All studies that have shown efficacy of theophylline in COPD were done with slow-release preparations.
Theophylline is less effective and less well tolerated than inhaled long-acting bronchodilators and is not recommended if those drugs are available and affordable.
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Addition of theophylline to salmeterol produces a greater increase in FEV1 and breathlessness than salmeterol alone.
Low dose theophylline reduces exacerbations but does not improve post-bronchodilator lung function.
Bronchodilators: Theophylline
Roflumilast – highly selective PDE4 inhibitor
Theophylline – nonselective weak PDE inhibitor มขีอ้จ ำกดั: safety และควำมทนต่อยำของผูป้่วย
PDE-4 = subtype ของ PDE พบมำกในบรเิวณที่มกีำรอกัเสบและกลำ้มเน้ือเรยีบของทำงเดนิหำยใจ กำรยบัยัง้ PDE-4 แบบจ ำเพำะเจำะจงจะออกฤทธิท์ ัง้ที่ mast cells และ neutrophils
MOA: เพิม่ระดบัของ cAMP โดยยบัยัง้เอนไซมท์ี่ท ำลำย cAMP, ยบัยัง้ mediator ที่ก่อใหเ้กดิกำรอกัเสบในทำงเดนิหำยใจ
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severe and very severe COPD (GOLD 3 and 4) and a history of exacerbations and chronic bronchitis
1 tab once daily.
กำรสบูบุหรีไ่ม่มผีลต่อค่ำเภสชัจลนศำสตรข์องยำ
SE: ปวดศรีษะ คลื่นไส ้ทอ้งเสยี สบัสน
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Roflumilast – highly selective PDE4 inhibitor
DAXAS®
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Tiotropium bromide
Indication: maintenance Tx of COPD not suitable for relief of acute bronchospasm Side effects: Tiotropium, like ipratropium (quaternary ammonium
compounds), is poorly absorbed from the GI tract and has very low systemic bioavailability. --- wide therapeutic margin
dryness of the mouth, a typical anticholinergic effect
Specific M1 and M3 Muscarinic Blockade
GOLD guideline: recommend for moderate or severe COPD use of regular tx of long acting bronchodilator, including tiotropium, rather than short acting bronchodilator
tiotropium 18 mcg OD with or without salmeterol should not be use together with other ipratropium
DPI (Handihaler)
Tiotropium bromide
Tiotropium
470 patients - stable COPD
3 month, randomized, double blind, once daily tiotropium vs. placebo
Conclusions: Increased FEV1 and FVC No tachyphylaxis Decreased rescue albuterol Decreased wheezing, SOB Dry mouth in 9.3%
Casaburi et al. CHEST 118:1294, 2000
Tiotroprium
• 1207 patients,
double blind,
randomized trial,
• qd tiotropium
vs. bid salmeterol
vs. placebo Conclusions: Tiotropium Fewer exacerbations Increased time to first exacerbation Fewer admissions Increased QOL
Brusasco et al. Thorax 58:399:2003
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Tiotropium versus LABA for stable COPD
37 Cochrane Database of Systematic Reviews 2012, Issue 9.
7 clinical studies totaling 12,223 patients with COPD LABA: formoterol, salmeterol, indacaterol
Tiotropium was more effective than LABAs as a
group in ….
• preventing COPD exacerbations and disease-
related hospitalisations
• no statistical differences between groups
in overall hospitalisation rates or mortality
during the study periods (3-12 months).
Inhaled Corticosteroids (ICS)
Regular treatment with ICS :
improves symptoms, lung function and QoL
reduces frequency of exacerbations for COPD patients with an FEV1 < 60% predicted.
ICS therapy is associated with an increased risk of pneumonia.
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• To reduce the frequency of exacerbation ICS ให้ร่วมกบั LABA more effective than the individual components in reducing exacerbations and improving LF
• Combination therapy is associated with an increased risk of pneumonia.
• LABA/ICS combination + tiotropium appears to provide additional benefits.
Combination: ICS + bronchodilator
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Meta-analysis: efficacy of ICS and LABA in a single inhaler with mono-component LABA alone in adults with COPD
Cochrane Database of Systematic Reviews 2012, Issue 9.
14 trials involving 11,794 people with COPD
• ICS/LABA inhalers reduced (compared with their LABA component alone) • frequency of exacerbations an average of one
exacerbation per year on a LABA to an average of 0.76 exacerbations per year on a combined inhaler.
• risk of mortality was similar between the treatments
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Meta-analysis: efficacy of ICS and LABA in a single inhaler with mono-component LABA alone in adults with COPD
Cochrane Database of Systematic Reviews 2012, Issue 9.
• There was evidence of an overall increased risk of pneumonia with combined inhalers, from around 3/100 people/year on LABA to 4/100/ year on combined inhalers.
• There was no significant difference between treatments in terms of hospitalisations
Systemic corticosteroids
จำก meta-analysis พบผูป้่วย stable COPD ที่ไดร้บั oral corticosteroid มคี่ำ FEV1 ดขีึน้ > 20% มมีำกกว่ำกลุ่มที่ไดร้บั placebo ประมำณ 10%
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Chronic treatment with systemic corticosteroids should be avoided
(an unfavorable benefit-to-risk ratio.
Identification and reduction of exposure to risk factors are important steps in prevention and treatment.
Individualized assessment of symptoms, airflow limitation, and future risk of exacerbations should be
incorporated into the management strategy.
Pharmacologic therapy is used to reduce symptoms,
reduce frequency and severity of exacerbations, and improve health status and exercise tolerance.
Global Strategy for Diagnosis, Management and Prevention of COPD
Manage Stable COPD: Key Points
© 2014 Global Initiative for Chronic Obstructive Lung Disease
LABA and LAMA are preferred over short-acting formulations.
Based on efficacy and side effects, inhaled bronchodilators are preferred over oral
bronchodilators.
Long-term treatment with ICS added to long-acting bronchodilators is recommended for patients with high risk of exacerbations.
Global Strategy for Diagnosis, Management and Prevention of COPD
Manage Stable COPD: Key Points
© 2014 Global Initiative for Chronic Obstructive Lung Disease
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Long-term monotherapy with OSC or ICS is not recommended in COPD.
The phospodiesterase-4 inhibitor roflumilast may be useful to reduce exacerbations for patients with FEV1 < 50% of predicted,
chronic bronchitis, and frequent exacerbations.
Global Strategy for Diagnosis, Management and Prevention of COPD
Manage Stable COPD: Key Points
© 2014 Global Initiative for Chronic Obstructive Lung Disease
Influenza vaccines can reduce serious illness. Pneumococcal polysaccharide vaccine is recommended for COPD patients (>65 years) and for COPD patients younger than age 65 with an FEV1 < 40% predicted.
The use of antibiotics, other than for treating infectious exacerbations of COPD and other bacterial infections, is currently not indicated.
Mucolytics: Patients with viscous sputum may benefit from
mucolytics; overall benefits are very small.
Antitussives: Not recommended.
Global Strategy for Diagnosis, Management and Prevention of COPD
Therapeutic Options: Other Pharmacologic Treatments
© 2014 Global Initiative for Chronic Obstructive Lung Disease
Global Strategy for Diagnosis, Management and Prevention of COPD
Manage Stable COPD: Non-pharmacologic
Patient Group
Essential Recommended Depending on local guidelines
A Smoking cessation Physical activity
Flu vaccination Pneumococcal
vaccination
B, C, D
Smoking cessation Pulmonary
rehabilitation Physical activity
Flu vaccination Pneumococcal
vaccination
© 2014 Global Initiative for Chronic Obstructive Lung Disease
Global Strategy for Diagnosis, Management and Prevention of COPD
Manage Stable COPD: Pharmacologic Therapy (Medications in each box are mentioned in alphabetical order, and therefore not necessarily in order of preference.)
Patient Recommended
First choice
Alternative choice Other Possible
Treatments
A
SAMA prn
or
SABA prn
LAMA
or
LABA
or
SABA and SAMA
Theophylline
B
LAMA
or
LABA LAMA and LABA
SABA and/or SAMA
Theophylline
C
ICS + LABA
or
LAMA
LAMA and LABA or
LAMA and PDE4-inh. or
LABA and PDE4-inh.
SABA and/or SAMA
Theophylline
D
ICS + LABA
and/or
LAMA
ICS + LABA and LAMA or
ICS+LABA and PDE4-inh. or
LAMA and LABA or
LAMA and PDE4-inh.
Carbocysteine
SABA and/or SAMA
Theophylline
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The most common causes of COPD exacerbations are viral upper respiratory tract infections and infection of the tracheobronchial tree.
SABA with or without SAMA are usually the
preferred bronchodilators for tx of an exacerbation.
Systemic corticosteroids and antibiotics can shorten recovery time, improve lung function and
arterial hypoxemia (PaO2), and reduce the risk of
early relapse, tx failure, and length of hospital stay.
Manage Exacerbations: Key Points
© 2014 Global Initiative for Chronic Obstructive Lung Disease
Antibiotics should be given to patients with:
Three cardinal symptoms: increased dyspnea, increased sputum volume, and increased sputum purulence.
Who require mechanical ventilation.
Oxygen: titrate to improve the patient’s
hypoxemia with a target saturation of 88-92%.
Manage Exacerbations:
© 2014 Global Initiative for Chronic Obstructive Lung Disease
Arterial blood gas measurements (in hospital): PaO2 < 8.0 kPa with or without PaCO2 > 6.7 kPa when breathing room air indicates respiratory failure.
Chest radiographs: useful to exclude alternative diagnoses.
ECG: may aid in the diagnosis of coexisting cardiac problems.
Whole blood count: identify polycythemia, anemia or bleeding.
Purulent sputum during an exacerbation: indication to begin empirical antibiotic treatment.
Biochemical tests: detect electrolyte disturbances, diabetes, and poor nutrition.
Spirometric tests: not recommended during an exacerbation.
Manage Exacerbations: Assessments
© 2014 Global Initiative for Chronic Obstructive Lung Disease
Prevention of COPD is to a large extent possible and should have high priority
Spirometry is required to make the diagnosis of COPD; the presence of a post-bronchodilator FEV1/FVC < 0.70 confirms the presence of persistent airflow limitation and thus of COPD
Combined assessment of symptoms and risk of exacerbations is the basis for non-pharmacologic and pharmacologic management of COPD
Treat COPD exacerbations to minimize their impact and to prevent the development of subsequent exacerbations
Summary
© 2014 Global Initiative for Chronic Obstructive Lung Disease