COPD Update

Dr.Veerendra SinghVice President UP Diabetes Association

Fellow UP Diabetes AssociationMember Indian College Of Allergy Asthma &

Immunology

Non communicable diseases are the biggest cause of death worldwide

WHO Report 2011

63 % of deaths in 2008 were due to NCDs– Cardiovascular diseases (48%)– Cancer (21%)– Chronic Respiratory Diseases (12%)– Diabetes (3%)

Last 5-6 decades

Last 2 decades

More deaths due to CDs than NCDs

e.g. TB, Malaria, HIV/AIDs, Leprosy, Dengue

Deaths due to CDs have declined sharply

More people now die due to NCDs

Chronic respiratory diseases e.g.COPD top this list

CDs: Communicable Diseases NCDs: Non-Communicable Diseases

Scenario in India

JAPI 2012; 60 (Suppl):5-7

Global Strategy for Diagnosis, Management and Prevention of COPD

Burden of COPD

COPD is a leading cause of morbidity and mortality worldwide.

The burden of COPD is projected to increase in coming decades due to continued exposure to COPD risk factors and the aging of the world’s population.

© 2014 Global Initiative for Chronic Obstructive Lung Disease

Crude estimates suggest there are 30 million COPD patients in India. [8] India contributes the highest COPD mortality in the world

COPD Burden in India

Definition of COPD Definition of COPD

© 2014 Global Initiative for Chronic Obstructive Lung Disease

PRIOR TO 2004• Chronic Bronchitis Clinical diagnosis as chronic productive cough for three months each in two successive years.• Emphysema Pathological diagnosis as the permanent enlargement of the airspaces and destruction of the airways• Asthma Loss of function

ATS/ERS GuidelinesNow first two of these (chronic bronchitis and emphysema)

are included under a single umbrella

COPD

Global Strategy for Diagnosis, Management and Prevention of COPD

Definition of COPD

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.

© 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

Asthma patients frequently have symptom free periods but COPD patient can never be asymptomatic

Professor Peter J. Barnes, MDNational Heart and Lung Institute, London UK

Global Strategy for Diagnosis, Management and Prevention of COPD

Mechanisms Underlying Airflow Limitation in COPD

Small Airways Disease

• Airway inflammation• Airway fibrosis• luminal plugs• Increased airway resistance

Parenchymal Destruction

• Loss of alveolar attachments• Decrease of elastic recoil

AIRFLOW LIMITATION

Global Strategy for Diagnosis, Management and Prevention of COPD

Risk Factors for COPD

Genes

Infections

Socio-economic status

Aging Populations© 2014 Global Initiative for Chronic Obstructive Lung Disease

Diagnosing COPD Diagnosing COPD

© 2014 Global Initiative for Chronic Obstructive Lung Disease

Exposure to risk factoreSmoking

occupation dust and fumes indoor/outdoor pollution

COPDSPIROMETRY: Required to establish

diagnosis

Global Strategy for Diagnosis, Management and Prevention of COPD

Diagnosis of COPD

è

© 2014 Global Initiative for Chronic Obstructive Lung Disease

Symptoms shortness of breath

chronic coughsputum production

Global Strategy for Diagnosis, Management and Prevention of COPD

Assessment of Airflow Limitation: SpirometrySpirometry should be performed

after the administration of an adequate dose of a short- acting inhaled bronchodilator to minimize variability.

A post-bronchodilator FEV1/FVC < 0.70 confirms the presence of airflow limitation.

© 2014 Global Initiative for Chronic Obstructive Lung Disease

Spirometry: Normal Trace Showing FEV1 and FVC

1 2 3 4 5 6

1

2

3

4

Volu

me,

liters

Time, sec

FVC5

1

FEV1 = 4L

FVC = 5L

FEV1/FVC = 0.8

© 2014 Global Initiative for Chronic Obstructive Lung Disease

Spirometry: Obstructive Disease

Volu

me,

liters

Time, seconds

5

4

3

2

1

1 2 3 4 5 6

FEV1 = 1.8L

FVC = 3.2L

FEV1/FVC = 0.56

Normal

Obstructive

© 2014 Global Initiative for Chronic Obstructive Lung Disease

Role of Chest X Ray in COPD

Near normal except a flat diaphragm and increased bronchovascular markings

Seldom diagnostic but valuable to exclude alternative diagnoses and comorbidities.

Global Strategy for Diagnosis, Management and Prevention of COPD

Additional Investigations

Lung Volumes and Diffusing Capacity: Help to characterize severity, but not essential to patient management. Oximetry and Arterial Blood Gases: evaluate oxygen saturation and need for supplemental oxygen therapy. Alpha-1 Antitrypsin Deficiency Screening: when COPD develops in patients of Caucasian descent under 45 years or with a strong family history of COPD.  

© 2013 Global Initiative for Chronic Obstructive Lung Disease

Severity of COPD Severity of COPD

© 2014 Global Initiative for Chronic Obstructive Lung Disease

• Determine the severity of the disease, its impact on the patient’s health status and the risk of future events (for example exacerbations) to guide therapy.

• Comorbidities occur frequently in COPD patients, and should be actively looked for.

Global Strategy for Diagnosis, Management and Prevention of COPD

Assessment of COPD: Goals

© 2014 Global Initiative for Chronic Obstructive Lung Disease

Global Strategy for Diagnosis, Management and Prevention of COPD

Assessment of COPD

Symptoms

Degree of airflow limitation using spirometry

Risk of exacerbations

Comorbidities

© 2014 Global Initiative for Chronic Obstructive Lung Disease

Global Strategy for Diagnosis, Management and Prevention of COPD

Assessment of COPD symptoms

© 2014 Global Initiative for Chronic Obstructive Lung Disease

COPD Assessment Test (CAT)

or

Clinical COPD Questionnaire (CCQ)

or

mMRC Breathlessness scale

COPD Assessment Test (CAT): An 8-item measure of health status impairment in COPD

Clinical COPD Questionnaire (CCQ): Self-administered questionnaire developed to measure clinical control in patients with COPD Modified British Medical Research Council (mMRC) Questionnaire: Breathlessness Measurement, relates well to other measures of health status and predicts future mortality risk.

Global Strategy for Diagnosis, Management and Prevention of COPD

Assessment of Symptoms

© 2014 Global Initiative for Chronic Obstructive Lung Disease

Global Strategy for Diagnosis, Management and Prevention of COPD

Modified MRC (mMRC)Questionnaire

mMRC Grade Symptoms Grade 0. Breathless with strenuous exercise. Grade 1. Breathless when hurrying on the level or walking up a slight hill.

Grade 2. Breathless when walking on own pace on the level. Grade 3. Breathless after walking about 100 meters on the level. Grade 4. Breathless with minimal exertion

© 2014 Global Initiative for Chronic Obstructive Lung Disease

Global Strategy for Diagnosis, Management and Prevention of COPD

Classification of Severity of Airflow Limitation in COPD*

FEV1/FVC < 0.70

Post-Bronchodilator FEV1

GOLD 1: Mild FEV1> 80% predicted

GOLD 2: Moderate (<80%) 50% - 79% predicted

GOLD 3: Severe (<50%) 30% - 49% predicted

GOLD 4: Very Severe < 30% predicted

© 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

Exacerbation history ≥ 2 exacerbations or

> 1 exacerbation leading to hospital admission

1 not leading to hospital admission)

0

Symptoms

(C) (D)

(A) (B)

CAT < 10

Gold 4

Gold 3

Gold 2

Gold 1

CAT > 10 mMRC 0–1 mMRC > 2

No exacerbations

exacerbation

spir

om

etr

ic a

sse

ssm

ent

Indicators of high risk Two or more exacerbations within last year

FEV1 < 50 % of predicted value

Hospitalization for a COPD exacerbation

Global Strategy for Diagnosis, Management and Prevention of COPD

Assessment of COPD

© 2014 Global Initiative for Chronic Obstructive Lung Disease

Therapeutic OptionsTherapeutic Options

© 2014 Global Initiative for Chronic Obstructive Lung Disease

Global Strategy for Diagnosis, Management and Prevention of COPD

Therapeutic Options: Key Points

Smoking cessation influences the natural history of COPD.

Regular physical activity should be encouraged to remain active.

© 2014 Global Initiative for Chronic Obstructive Lung Disease

Appropriate pharmacologic therapy can reduce COPD symptoms, reduce the frequency and severity of exacerbations, and improve health status and exercise tolerance.

None of the existing medications has been shown to modify the long-term decline in lung function.

Influenza and pneumococcal vaccination should be offered depending on local guidelines.

Global Strategy for Diagnosis, Management and Prevention of COPD

Therapeutic Options: Key Points

© 2014 Global Initiative for Chronic Obstructive Lung Disease

Bronchodilator medications are central to the symptomatic

management of COPD

Global Strategy for Diagnosis, Management and Prevention of COPD

Therapeutic Options: Bronchodilators

© 2014 Global Initiative for Chronic Obstructive Lung Disease

Bronchodilators in COPD

Beta 2 Agonists Short Acting Beta 2 agonists (SABA)

Salbutamol ,Terbutaline Long Acitng Beta 2 agonists (LABA)

Formoterol ,Salmeterol,Indacaterol, Vilanterol

Anticholinergics Short Acting Muscarinic Antagonist (SAMA)

Ipratropium ,Oxitropium Long Acting Muscarinic Antagonists (LAMA)

Tiotropium, Aclidinium, glycopyronnium,Umeclidinium)

SABA & SAMA for short term use in acute cases

LABA & LAMA for long term maintenance therapy

MABAs are a type of agent that have both β2-agonist and anticholinergic activity in one

drug.

Long-acting inhaled bronchodilators reduce exacerbations and related hospitalizations

and improve symptoms and health status.

Combining bronchodilators of different pharmacological classes may improve efficacy and decrease the risk of side effects.

Global Strategy for Diagnosis, Management and Prevention of COPD

Therapeutic Options: Bronchodilators

© 2013 Global Initiative for Chronic Obstructive Lung Disease

Inhaled Corticosteroids (ICS)

Regular treatment with inhaled corticosteroids improves symptoms, lung function and quality of life and reduces frequency of exacerbations for COPD patients with an FEV1< 60% predicted.

Inhaled corticosteroid therapy is associated with an increased risk of pneumonia.

Global Strategy for Diagnosis, Management and Prevention of COPD

Inhaled Corticosteroids

© 2014 Global Initiative for Chronic Obstructive Lung Disease

Chronic treatment with systemic corticosteroids should be avoided because of an unfavorable benefit-to-risk ratio.

Global Strategy for Diagnosis, Management and Prevention of COPD

Therapeutic Options: Systemic Corticosteroids

© 2014 Global Initiative for Chronic Obstructive Lung Disease

Global Strategy for Diagnosis, Management and Prevention of COPD

Therapeutic Options: Theophylline

Theophylline is less effective and less well tolerated than inhaled long-acting bronchodilators and is not recommended if those drugs are available and affordable.

Low dose theophylline reduces exacerbations but does not improve post-bronchodilator lung function.

© 2014 Global Initiative for Chronic Obstructive Lung Disease

In patients with severe and very severe COPD (GOLD 3 and 4) and a history of exacerbations and chronic bronchitis, the phospodiesterase-4 inhibitor, roflumilast, reduces exacerbations.

Global Strategy for Diagnosis, Management and Prevention of COPD

Phosphodiesterase-4 Inhibitors

© 2014 Global Initiative for Chronic Obstructive Lung Disease

Influenza vaccines is recommended for COPD patients 65 years and older and for younger than age 65 with FEV1< 40% predicted.

The use of antibiotics, other than for treating infectious exacerbations of COPD and other bacterial infections, is currently not indicated.

Global Strategy for Diagnosis, Management and Prevention of COPD

Therapeutic Options: Other Pharmacologic Treatments

© 2014 Global Initiative for Chronic Obstructive Lung Disease

Alpha-1 antitrypsin augmentation therapy: not recommended for patients with COPD that is unrelated to the genetic deficiency.

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

Oxygen Therapy: The long-term administration of oxygen (> 15 hours per day) to patients with chronic respiratory failure.

Ventilatory Support: Combination of noninvasive ventilation (NIV) with long-term oxygen therapy may be of some use in a selected subset of patients.

Global Strategy for Diagnosis, Management and Prevention of COPD

Therapeutic Options: Other Treatments

© 2014 Global Initiative for Chronic Obstructive Lung Disease

Stable COPDStable COPD

© 2014 Global Initiative for Chronic Obstructive Lung Disease

Exa

cerb

atio

ns

per

ye

ar

0

CAT < 10mMRC 0-1

GOLD 4

CAT >10 mMRC >2

GOLD 3

GOLD 2

GOLD 1

SAMA prnor

SABA prn

LABA or

LAMA

ICS + LABAor

LAMA

Global Strategy for Diagnosis, Management and Prevention of COPD

Manage Stable COPD: PharmacologicTherapyRECOMMENDED FIRST CHOICE

A B

DC

ICS + LABAand/orLAMA

© 2014 Global Initiative for Chronic Obstructive Lung Disease

2 or more or> 1 leading to hospital admission

1 (not leading to hospital admission)

• FEV1/FVC < 0.70

• FEV1 ≥ 80% predicted

• FEV1/FVC < 0.70

• ≤ FEV1 50-80% predicted

• FEV1/FVC < 0.70

• ≤ FEV1 30- 50% predicted

• FEV1/FVC < 0.70

• FEV1 < 30% predicted or FEV1 < 50% predicted plus chronic respiratory failure

Add regular treatment with long-acting bronchodilators; Begin Pulmonary Rehabilitation

Add inhaled glucocorticosteroids if repeated acute exacerbations

Add LTOT for chronic hypoxemia.Consider surgical options

III: SevereI: MildII: Moderate

IV: Very Severe

Active reduction of risk factor(s); smoking cessation, flu vaccination

Add short-acting bronchodilator (as needed)

GOLD Guidelines

ComorbiditiesComorbidities

© 2014 Global Initiative for Chronic Obstructive Lung Disease

Global Strategy for Diagnosis, Management and Prevention of COPD

COPD Comorbidities

• Cardiovascular diseases• Osteoporosis• Respiratory infections• Anxiety and Depression• Diabetes• Lung cancer• Bronchiectasis

© 2014 Global Initiative for Chronic Obstructive Lung Disease

In general, presence of comorbidities

should not alter COPD treatment and

comorbidities should be treated as if the

patient did not have COPD. 

Global Strategy for Diagnosis, Management and Prevention of COPD

ManageComorbidities

© 2014 Global Initiative for Chronic Obstructive Lung Disease

Cardiovascular diseases (ischemic heart disease, heart failure, atrial fibrillation, and hypertension) are major comorbidity in COPD. Benefits of cardioselective beta-blocker treatment in heart failure outweigh potential risk even in patients with severe COPD. 

Global Strategy for Diagnosis, Management and Prevention of COPD

ManageComorbidities

© 2014 Global Initiative for Chronic Obstructive Lung Disease

ExacerbationsExacerbations

© 2014 Global Initiative for Chronic Obstructive Lung Disease

The most common causes of COPD exacerbations are viral upper respiratory tract infections and infection of the tracheobronchial tree.

The goal of treatment is to minimize the impact of the current exacerbation and to prevent the development of subsequent exacerbations.

Global Strategy for Diagnosis, Management and Prevention of COPD

Manage Exacerbations: Key Points

© 2014 Global Initiative for Chronic Obstructive Lung Disease

Prevention of exacerbations

Quit smoking Long acting broncodilators Inhaled corticosteroids Pneumococcal and influenza vaccine PDE-4 inhibitors: Roflumilast Maintenece of physical activity Managing comorbidities

© 2014 Global Initiative for Chronic Obstructive Lung Disease

Asthma COPD Overlap

Asthma COPD Overlap

© 2014 Global Initiative for Chronic Obstructive Lung Disease

This is probably the group in which triple therapy may be very effective

Smoking is by far recognized to be most important risk

factor for development of COPD

But smoking is not the only risk factor!

Biomass smoke

Occupational exposure

Outdoor pollution

3 billion people exposed to biomass fuel worldwide

Long-term exposure to ambient air pollutants increased the risk of COPD by 2-fold

Eur J Epidemiol 2003; 18: 45-53 , JAPI 2012; 60 (Suppl):5-7

Non smokers reported greater lifetime burdens of respiratory disease

10-12% of individuals with COPD have never smoked

Indian Edition /Vol.4,No.1,2014

COPD in non smokers

• In INSEARCH phase II study, approximately 60% of chronic bronchitis patients were nonsmokers.

• Respiratory symptoms were reported in 13% of 3,608 nonsmoking women involved in domestic cooking.

• Mosquito coil One mosquito coil emitts particulate matter equivalent to

those with around 100 cigarettes

• Pulmonary tuberculosisPrevalence of airflow obstruction varies from 28 to 68%.

• Asthma 10-fold increased risk of chronic bronchitis and 17-fold

increased risk of emphysema

• Alpha-1 antitrypsin deficiency and other genetic factors

COPD in non smokers:Other causes

25 years of COPD Management1990-2015

1990s: Salbutamol Theophyllin Steroids alone with

salbutamol LABA :salmeterol or

formeterol anticholinergics

2015: Anticholinergics LABA SR Theophyllin ICS alone or in

combination with LABA

Salbutamol only need based

Glimpses of new researches in COPD

Dual bronchodilation vs an ICS-LABA

in milder patients in patients with more severe disease

Both studies showed that LABA/LAMA seems to be more efficient than the LABA-ICS combinations.

Long term prophylactic antibiotics

Cochrane Database Syst Rev. 2013 Nov 28;11:CD009764.

Prophylactic antibiotic therapy for chronic obstructive pulmonary disease (COPD).Herath SC1, Poole P.

• Seven RCTs involving 3170 patients were included in this systematic review. All studies were published between 2001 and 2011.

• The antibiotics investigated were azithromycin, erythromycin, clarithromycin and moxifloxacin.

• With use of continuous prophylactic antibiotics the number of patients experiencing an exacerbation was reduced (odds ratio (OR) 0.55; 95% confidence interval (CI) 0.39 to 0.77, 3 studies, 1262 participants, high quality).

• Use of continuous prophylactic antibiotics results in a clinically significant benefit in reducing exacerbations in COPD patients. All trials of continuous antibiotics used macrolides hence the noted benefit applies only to the use of continuous macrolide antibiotics. The impact of pulsed antibiotics remains uncertain and requires further research.The

Use of continuous prophylactic antibiotics results in a clinically significant benefit in reducing exacerbations in COPD patients.

Respir Med. 2013 Sep;107(9):1385-92. doi: 10.1016/j.rmed.2013.05.004. Epub 2013 Jun 12.

A meta-analysis on the prophylactic use of macrolide antibiotics for the prevention of disease exacerbations in patients with Chronic Obstructive Pulmonary Disease.Donath E1, Chaudhry A, Hernandez-Aya LF, Lit L.

• INTRODUCTION:• Macrolides are of unique interest in preventing COPD exacerbations because they possess a variety of antibacterial, antiviral and anti-

inflammatory properties. Recent research has generated renewed interest in prophylactic macrolides to reduce the risk of COPD exacerbations. Little is known about how well these recent findings fit within the context of previous research on this subject. The purpose of this article is to evaluate, via exploratory meta-analysis, whether the overall consensus favors prophylactic macrolides for prevention of COPD exacerbations.

• METHODS:• EMBASE, Cochrane and Medline databases were searched for all relevant randomized controlled trials (RCTs). Six RCTs were identified.

The primary endpoint was incidence of COPD exacerbations. Secondary endpoints including mortality, hospitalization rates, adverse events and likelihood of having at least one COPD exacerbation were also examined.

• RESULTS:• There was a 37% relative risk reduction (RR = 0.63, 95% CI: 0.45-0.87, p value = 0.005) in COPD exacerbations among patients taking

macrolides compared to placebo. Furthermore, there was a 21% reduced risk of hospitalization (RR = 0.79, 95% CI: 0.69-0.90, p-value = 0.01) and 68% reduced risk of having at least one COPD exacerbation (RR = 0.34, 95% CI 0.21-0.54, p-value = 0.001) among patients taking macrolides versus placebo. There was also a trend toward decreased mortality and increased adverse events among patients taking macrolides but these were not statistically significant.

• CONCLUSIONS:• Prophylactic macrolides are an effective approach for reducing incident COPD exacerbations. There were several limitations to this

study including a lack of consistent adverse event reporting and some degree of clinical and statistical heterogeneity between studies

There was a 37% relative risk reduction (RR = 0.63, 95% CI: 0.45-0.87, p value = 0.005) in COPD exacerbations among patients taking macrolides compared to placebo. Furthermore, there was a 21% reduced risk of hospitalization

PLoS One. 2015 Mar 26;10(3):e0121257. doi: 10.1371/journal.pone.0121257. eCollection 2015.

Prophylactic use of macrolide antibiotics for the prevention of chronic obstructive pulmonary disease exacerbation: a meta-analysis.Ni W1, Shao X1, Cai X1, Wei C1, Cui J1, Wang R2, Liu Y1.

• BACKGROUND:• Acute exacerbations of chronic obstructive pulmonary disease (AECOPDs) can lead to high frequencies and rates of hospitalization and

mortality. Macrolides are a class of antibiotics that possess both antimicrobial and anti-inflammatory properties. Since the occurrence of AECOPDs is associated with aggravation of airway inflammation and bacterial infections, prophylactic macrolide treatment may be an effective approach towards the prevention of AECOPDs.

• METHODS:• We systemically searched the PubMed, Embase and Cochrane Library databases to identify randomized controlled trials (RCTs) that

evaluated the effect of prophylactic macrolide therapy on the prevention of AECOPDs. The primary outcomes were the total number of patients with one or more exacerbations as well as the rate of exacerbations per patient per year.

• RESULTS:• Nine RCTs comprising 1666 patients met the inclusion criteria. Pooled evidence showed macrolides could reduce the frequency of

exacerbations in patients with COPD by both unweighted (RR = 0.70; 95% CI: 0.56-0.87; P < 0.01) and weighted approaches (RR = 0.58, 95% CI: 0.43-0.78, P < 0.01). Subgroup analysis showed only 6-12 months of erythromycin or azithromycin therapy could be effective. Moreover, among studies with 6-12 months of azithromycin therapy, both the daily dosing regimen and the intermittent regimen significantly reduced exacerbation rates. The overall number of hospitalizations and the all-cause rate of death were not significantly different between the treatment and control groups. A tendency for more adverse events was found in the treatment groups (OR = 1.55, 95%CI: 1.003-2.39, P = 0.049).

• CONCLUSIONS:• Our results suggest 6-12 months erythromycin or azithromycin therapy could effectively reduce the frequency of exacerbations in

patients with COPD. However, Long-term treatment may bring increased adverse events and the emergence of macrolide-resistance. A recommendation for the prophylactic use of macrolide therapy should weigh both the advantages and disadvantages.

6-12 months erythromycin or azithromycin therapy could effectively reduce the frequency of exacerbations in patients with COPD

N-Acetyl Cystein in COPD

Int J Chron Obstruct Pulmon Dis. 2014 Aug 6;9:825-36. doi: 10.2147/COPD.S51057. eCollection 2014.

Update on the pathological processes, molecular biology, and clinical utility of N-acetylcysteine in chronic obstructive pulmonary disease.Tse HN1, Tseng CZ1.

N-acetylcysteine (NAC) is a mucolytic agent with both antioxidant and anti-inflammatory properties. This paper also reviews the use of NAC in patients with COPD, especially the dose-dependent properties of NAC, eg, its effects on lung function and the exacerbation rate in patients with the disease. Earlier data from BRONCUS (the Bronchitis Randomized on NAC Cost-Utility Study) did not suggest that NAC was beneficial in patients with COPD, only indicating that it reduced exacerbation in an "inhaled steroid-naïve" subgroup. With regard to the dose-dependent properties of NAC, two recent randomized controlled Chinese trials suggested that high-dose NAC (1,200 mg daily) can reduce exacerbations in patients with COPD, especially in those with an earlier (moderately severe) stage of disease, and also in those who are at high risk of exacerbations. However, there was no significant effect on symptoms or quality of life in patients receiving NAC. Further studies are warranted to investigate the effect of NAC at higher doses in non-Chinese patients with COPD.

High-dose NAC (1,200 mg daily) can reduce exacerbations in patients with COPD, especially in those with an earlier (moderately severe) stage of disease, and also in those who are at high risk of exacerbations.

Statins in COPD

Int J Clin Pract. 2008 Sep;62(9):1373-8.

Statins may reduce episodes of exacerbation and the requirement for intubation in patients with COPD: evidence from a retrospective cohort study.Blamoun AI1, Batty GN, DeBari VA, Rashid AO, Sheikh M, Khan MA.

• This is a retrospective cohort study of 185 patients with COPD exacerbation, with a 1-year follow-up. Outcomes examined were repeat hospitalisation and intubations for COPD exacerbation. Baseline characteristics for which the p-value was < or = 0.10 were considered as covariates for inclusion in a multivariate model.

• RESULTS:• The statin group had fewer episodes of exacerbation and required intubation fewer times than the

subjects not receiving statins (p < 0.0001 for both outcomes). Unadjusted odds ratios (OR) for no statin use vs. statin use were 9.54 (95% CI: 4.54-20.02) for exacerbation and 10.47 (CI: 4.56-24.01) for intubation. The OR, adjusted for the use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (ORa), were 2.35 (CI: 1.01-5.50) for non-statin users exhibiting an exacerbation and 10.36 (CI: 2.77-38.76) for this group requiring intubation, compared with statin users. Similarly, ORa for long-acting beta(2) agonists as a covariate were 3.01 (CI: 1.46-6.10) for exacerbation and 8.89 (CI: 3.67-21.32) for intubation. Time to outcome during the observation period was reduced by statins with the hazard ratio (HR) for exacerbation of 0.19 (CI: 0.06-0.14); HR for statins reducing intubation was 0.14 (95% CI: 0.10-0.30).

• CONCLUSIONS:• These data suggest that the use of statins may be associated with lower incidence of both

exacerbations and intubations in patients with COPD.

These data suggest that the use of statins may be associated with lower incidence of both exacerbations and intubations in patients with COPD.

Chest. 2009 Sep;136(3):734-43. doi: 10.1378/chest.09-0194. Epub 2009 Apr 17.Statins in COPD: a systematic review.Janda S1, Park K, FitzGerald JM, Etminan M, Swiston J.

• The 3-hydroxy 3-methylglutaryl coenzyme A reductase inhibitors (ie, statins) are widely used for the treatment of patients with hypercholesterolemia and cardiovascular disease. Emerging evidence suggests a beneficial effect of statins on the morbidity and mortality of patients with COPD. The objective of this study was to perform a systematic review of the literature evaluating the effect of statin therapy on outcomes in patients with COPD.

• METHODS:• Medline, Excerpta Medica Database, PapersFirst, and the Cochrane collaboration and Cochrane Register of controlled trials

were searched. Randomized controlled trials (RCTs), observational cohort studies, case-control studies, and population-based analyses were considered for inclusion.

• RESULTS:• Nine studies were identified for review (four retrospective cohorts, one nested case-control study of a retrospective cohort,

one retrospective cohort and case series, two population-based analyses, and one RCT). All studies showed a benefit from statin therapy for various outcomes in COPD patients, including the number of COPD exacerbations (n = 3), the number of and time to COPD-related intubations (n = 1),pulmonary function (eg, FEV(1) and FVC) [n = 1], exercise capacity (n = 1), mortality from COPD (n = 2), and all-cause mortality (n = 3). No studies describing a negative or neutral effect from statin therapy on outcomes in COPD patients were identified.

• CONCLUSIONS:• The current literature collectively suggests that statins may have a beneficial role in the treatment of COPD. However, the

majority of published studies have inherent methodological limitations of retrospective studies and population-based analyses. There is a need for prospective interventional trials designed specifically to assess the impact of statins on clinically relevant outcomes in COPD.

The current literature collectively suggests that statins may have a beneficial role in the treatment of COPD.

Beta Blockers in COPD

PLoS One. 2014 Nov 26;9(11):e113048. doi: 10.1371/journal.pone.0113048. eCollection 2014.

Beta-blockers reduced the risk of mortality and exacerbation in patients with COPD: a meta-analysis of observational studies.Du Q1, Sun Y1, Ding N1, Lu L1, Chen Y1.

• An extensive search of the EMBASE, MEDLINE and Cochrane was performed to retrieve the studies of beta-blockers treatment in patients with COPD. The random effects model meta-analysis was used to evaluate effect on overall mortality and exacerbation of COPD.

• Fifteen original observational cohort studies with a follow-up time from 1 to 7.2 years were included. The results revealed that beta-blockers treatment significantly decreased the risk of overall mortality and exacerbation of COPD. The relative risk (RR) for overall mortality was 0.72 (0.63 to 0.83), and for exacerbation of COPD was 0.63 (0.57 to 0.71). In subgroup analysis of COPD patients with coronary heart disease or heart failure, the risk for overall mortality was 0.64 (0.54-0.76) and 0.74 (0.58-0.93), respectively.

• The findings of this meta-analysis confirmed that beta-blocker use in patients with COPD may not only decrease the risk of overall mortality but also reduce the risk of exacerbation of COPD. Beta-blocker prescription for cardiovascular diseases needs to improve in COPD patients.

Beta-blocker use in patients with COPD may not only decrease the risk of overall mortality but also reduce the risk of exacerbation of COPD.

Ann Pharmacother. 2004 Jan;38(1):142-5.

Use of beta-blockers in patients with COPD.Andrus MR1, Holloway KP, Clark DB.

• To evaluate the safety and cardiovascular benefits of beta-blocker therapy in patients with chronic obstructive pulmonary disease(COPD).

• DATA SOURCES:• Clinical literature was accessed through MEDLINE (1966-February 2003). Key

search terms included chronic obstructive pulmonary disease and adrenergic beta-antagonists.

• DATA SYNTHESIS:• beta-Blockers are often avoided in patients with COPD because of fear of

bronchoconstriction, despite the known cardiovascular mortality benefits. A review of studies evaluating the use of beta-blockers in COPD was undertaken.

• CONCLUSIONS:• The literature supports the safety and mortality benefits of using beta-

blockers in COPD. Patients with mild to moderate COPDshould receive cardioselective beta-blocker therapy when a strong indication exists.

The literature supports the safety and mortality benefits of using beta-blockers in COPD. Patients with mild to moderate COPDshould receive cardioselective beta-blocker therapy when a strong indication exists.

Vit.D Deficiency in COPD

Respir Res. 2014 Dec 13;15(1):131. doi: 10.1186/s12931-014-0131-0.

Severe vitamin D deficiency is associated with frequent exacerbations and hospitalization in COPD patients.Malinovschi A1, Masoero M2, Bellocchia M3, Ciuffreda A4, Solidoro P5, Mattei A6, Mercante L7, Heffler E8, Rolla G9, Bucca C10.

• Serum vitamin D (25-hydroxyvitamin D) levels were measured in 97 COPD patients and related to lung function, comorbidities, FEV1 decline, AECOPD and hospital admission during the previous year.

• Most patients (96%) had vitamin D deficiency, which was severe in 35 (36%). No significant relationship was found between vitamin Dand FEV1 or annual FEV1 decline. No difference between patients with and without severe vitamin D deficiency was found in age, gender, BMI, smoking history, lung function, and comorbidities, apart from osteoporosis (60.9% in severe deficiency vs 22.7%, p = 0.001). In multiple logistic regression models, severe deficiency was independently associated with AECOPD [adjusted odds ratios (aOR) of 30.5 (95% CI 5.55, 168), p < 0.001] and hospitalization [aOR 3.83 (95% CI 1.29, 11.4), p = 0.02]. The odds ratio of being a frequent exacerbator if having severe vitamin Ddeficiency was 18.1 (95% CI 4.98, 65.8) (p < 0.001), while that of hospitalization was 4.57 (95% CI 1.83, 11.4) (p = 0.001).

• In COPD patients severe vitamin D deficiency was related to more frequent disease exacerbations and hospitalization.

In COPD patients severe vitamin D deficiency was related to more frequent disease exacerbations and hospitalization.

American Journal of Respiratory and Critical Care Medicine, Vol. 185, No. 3 (2012),

Vitamin D and Chronic Obstructive Pulmonary Disease: Justified Optimism or False Hope?Seif O. Shaheen Ph.D. , and Adrian R. Martineau Ph.D.

•Data from observational studies are conflicting, both from studies of patients with COPD and from population-based research.•A recent cross-sectional study observed a positive association between 25(OH)D concentrations and FEV1 in patients with COPD (12). In contrast, a longitudinal study of continuous smokers with COPD found no difference in baseline 25(OH)D concentrations between individuals who had a rapid decline in lung function and those with a slow decline•To date, population-based data on the relation of 25(OH)D to lung function decline are lacking, although preliminary data, reported in the form of an abstract, have suggested a possible relation between lower vitamin D status and faster decline in the FEV1/FVC ratio (but not FEV1) in an elderly population (16).

To date, population-based data on the relation of 25(OH)D to lung function decline are lacking, although preliminary data suggested a possible relation between lower vitamin D status and faster decline in the FEV1/FVC ratio (but not FEV1) in an elderly population.

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