Seth Haslam, PharmD Candidate 2012 Idaho State University College of Pharmacy
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Are β-blockers Beneficial in Patients with Chronic Obstructive Pulmonary Disease (COPD)? Seth Haslam, PharmD Candidate 2012 Idaho State University College of Pharmacy
Seth Haslam, PharmD Candidate 2012 Idaho State University College of Pharmacy
Seth Haslam, PharmD Candidate 2012 Idaho State University
College of Pharmacy
Slide 2
Personal Disclaimer I claim no financial interests or
relationships which would influence the body of my
presentation
Slide 3
COPD Disease Statistics In 1990, chronic obstructive pulmonary
disease (COPD) was ranked as the sixth leading cause of death
worldwide By 2030, COPD will be the fourth leading cause of death
worldwide As of 2007, COPD is the fourth leading cause of death in
the United States
Slide 4
Objectives I. Review the etiology and pathophysiology of COPD
II. Become familiar with recently updated (2010) COPD treatment
guidelines III. Analyze use of -blockers in COPD patients IV.
Evaluate current literature dealing with -blocker use in the COPD
patient population V. Recommendations for clinical practice from
KMC pulmonologists
Slide 5
I. What is COPD? Chronic Obstructive Pulmonary Disease
Characterized by significant airflow limitation that is not fully
reversible Airflow limitation is progressive and associated with
hyper-responsiveness to noxious stimuli Extra-pulmonary effects may
contribute to the severity of the disease in individual patients
Traditionally was referred to as chronic bronchitis or emphysema
Emphysema and chronic bronchitis describe two components of the
overall disease state
Slide 6
I. COPD Risk Factors When assessing risk, the total burden of
inhaled particles should be considered Risks Tobacco smoke most
common risk factor Occupational dusts and chemicals Organic and
inorganic dusts Chemical agents and fumes Genetics alpha-1
antitrypsin deficiency Indoor air pollution Crop residues Coal
burning stoves Outdoor air pollution Urban air pollution Fossil
fuel combustion
Slide 7
I. Pathophysiology of COPD Chronic exposure to particulates
Recruitment of cytokines in response to noxious stimuli Exposure to
particulates Proinflammatory cells involved: Neutrophils,
macrophages, and lymphocytes Proinflammatory mediators involved:
Leukotrienes, tumor necrosis factor, interleukins Lung inflammation
Oxidative stress Small airway fibrosis, mucus hypersecretion,
activation of inflammatory genes Protease-antiprotease imbalance
alveolar destruction COPD pathology
Slide 8
I. COPD vs. Asthma COPDAsthmaComments Proinflammatory cell
involvement: Primarily neutrophils Primarily eosinophilsReason for
differences in response to therapy Pathology:Small airway fibrosis
and alveolar destruction Bronchoconstriction and airway
hyperresponsiveness COPD=obstructive Asthma=restrictive Airflow
limitation:Not fully reversible ReversibleSevere asthma may not be
fully reversible
Slide 9
I. Diagnosis of COPD A diagnosis of COPD requires presence of
these three symptoms plus: A history of exposure to risk factors
Spirometric evidence of disease Symptoms Chronic cough Sputum
production Dyspnea upon exertion
Slide 10
I. COPD Pathophysiology and Etiology: Summary COPD is
characterized by air flow limitation that is not fully reversible
The pathophysiologic process of COPD: Exposure to particles Lung
inflammation Small airway fibrosis and alveolar destruction COPD is
differentiated from asthma by: Type of proinflammatory cells
involved Disease pathology Reversibility of airflow limitation
Diagnosis of COPD: Dyspnea upon exertion, chronic cough, sputum
production
Slide 11
II. Treatment of COPD: Objectives Review COPD pharmacotherapy
options -agonists Anticholinergics Methylxanthines
Glucocorticosteroids PD4 inhibitors Review COPD treatment
guidelines Stepwise treatment and maintenance Treatment of
exacerbations
Slide 12
II. Current Treatment Options for COPD Bronchodilators:
2-agonists, MOA: relax airway smooth muscle by stimulating 2
receptors Short acting: albuterol (ProAir, Proventil), levalbuterol
(Xopenex) Long acting: salmeterol (Serevent), formoterol (Foradil)
Anticholinergics, MOA: antagonize acetylcholines effect on M3
receptors producing relaxation of airway smooth muscle Short
acting: ipratropium (Atrovent) Long acting: tiotropium (Spiriva)
Methylxanthines, MOA: nonselective phosphodiesterase inhibitor,
increase in cAMP, relaxation of airway smooth muscle Long acting
formulation: theophylline (Theo-24, Uniphyl) Bronchodilators are
central to COPD management
Slide 13
II. Current Treatment Options for COPD Inhaled and oral
corticosteroids, MOA: inhibits multiple inflammatory cytokines,
reduces airway inflammation Benefit in COPD is less pronounced than
in asthma Use is reserved for patients with repeated exacerbations
Combination with long acting 2-agonist is more effective than
either agent alone Phosphodiesterase-4 inhibitors, MOA: inhibit
PD4, increase cAMP, reduce airway inflammation roflumilast
(Daliresp) FDA indicated for prevention of COPD exacerbations
Slide 14
II. Current Treatment Options for COPD Influenza vaccine Proven
to drastically reduce serious illness and death in COPD patients
0.5 mL IM annually Pneumococcal vaccine Recommended in all COPD
patients > 65 years 0.5 mL IM/SC once, repeat once after 5 years
in immunocompromised patients If patient is > 65 years and first
dose was given when patient was < 65 years, give repeat dose (at
least 5 years apart) *Vaccine Recommendations for COPD patients per
GOLD
Slide 15
II. Stages of COPD FEV: forced expiratory volume in one second
FVC: forced vital capacity COPD Severity Classification I. MildII.
ModerateIII. SevereIV. Very Severe FEV/FVC < 0.70 FEV > 0.80
predicted FEV/FVC < 0.70 50% FEV 80% predicted FEV/FVC < 0.70
30% FEV 50% predicted FEV/FVC < 0.70 FEV < 30% predicted or
FEV < 50% predicted plus chronic respiratory failure
Slide 16
II. Stepwise Treatment of COPD I. MildII. ModerateIII.
SevereIV. Very Severe Active reduction of risk factor(s); influenza
vaccination Add short acting bronchodilator(s) when needed:
albuterol (ProAir, Proventil), levalbuterol (Xopenex), ipratropium
(Atrovent) Add regular treatment with long-acting
bronchodilator(s): tiotropium (Spiriva), salmeterol (Serevent),
formoterol (Foradil), theophylline (Uniphyl) Add physician assisted
exercise training Add inhaled corticosteroids if repeated
exacerbations Combination products appropriate:
fluticasone/salmeterol (Advair), budesonide/formoterol (Symbicort)
Add long term oxygen if chronic respiratory failure
Slide 17
II. Treatment of COPD Exacerbations Home management Increase
the dose and frequency of short acting bronchodilators Add
anticholinergics until symptoms improve Corticosteroids recommended
if FEV < 50% predicted Prednisone 30-40 mg PO daily x 7-10 days
Antibiotics are recommended in patients who have: Increased dyspnea
Increased sputum volume Increased sputum purulence
Slide 18
II. Treatment of COPD: Summary COPD pharmacotherapeutic options
include: -agonists Anticholinergics Methylxanthines
Glucocorticosteroids PD-4 inhibitors Vaccines and stepwise
treatment are important in preventing COPD exacerbations Increasing
dose of short acting bronchodilator and starting
glucocorticosteroids and/or antibiotics may be required in COPD
exacerbations
Slide 19
III. COPD and -blockers: Objectives Discuss the prevalence of
cardiovascular disease in the COPD patient population Analyze the
use of -blockers in the COPD patient population Avoidance of
-blocker use in COPD patients Safety of -blocker use in COPD
population
Slide 20
III. Cardiovascular Disease and COPD Patients with COPD are at
increased risk for multiple diseases especially cardiovascular
disease Most deaths in patients with COPD attributed to
cardiovascular disease (CVD) High prevalence rate of heart failure
in older patients with COPD One study documented a 20.5% prevalence
of heart failure in patients with stable chronic COPD Heart
failure, and other co-morbidities, can often go undiagnosed in
patients with COPD Symptoms of COPD can mask other
co-morbidities
Slide 21
III. -blockers and COPD -blockers are known to improve survival
of patients with CVD and heart failure Despite high prevalence of
CVD and heart failure in COPD patients, -blocker use is commonly
avoided -blockers have been avoided in COPD due to: Risk of acute
bronchospasm Evidence of reduction in FEV 1 Increased airway
hyperresponsiveness Inhibition of bronchodilator response due to
competition for 2 receptors
Slide 22
III. -receptor Pharmacology: Review Cardiac muscle Increased
inotropy and chronotropy Bronchial smooth muscle
Bronchodilation
Slide 23
III. Cardiodselective and Non- Cardioselective -blockers
-blockers that have a greater affinity for 1 -receptors than 2
-receptors are termed cardioselective Cardioselective -blockers are
the preferred agents in treatment of patients with CVD and CHF
Cardioselective -blockersNon-cardioselective -blockers Atenolol
(Tenormin) Metoprolol (Lopressor) Carvedilol (Coreg) Nebivolol
(Bystolic) Propranolol (Inderal) Nadolol (Corgard) Sotalol
(Betapace)
Slide 24
III. Meta-Analysis Cardioselective beta-blockers in patients
with reactive airway disease: a meta-analysis. Ann Intern Med.
Salpeter et al. 2002. The meta-analysis included all studies that
dealt with the effects of -blockers on: FEV 1 COPD symptoms Use of
inhaled 1 agonists Included only studies that were randomized,
blinded, and placebo-controlled All studies from 1966 to May
2001
Slide 25
III. Meta-Analysis Authors conclusion: -blockers may be safe in
patients with mild to moderate COPD After publication, many
researchers became curious about potential benefit of -blockers in
COPD
Slide 26
III. COPD and -blockers Concerns about -blocker use and COPD
still exist The product label information for Toprol-XL (metoprolol
succinate), a cardioselective -blocker, contains the following
warning: Patients with bronchospastic disease should, in general,
not receive -blockers Similar warnings found in other -blocker
product label information
Slide 27
III. COPD and -blockers: Summary High prevalence rate of CVD
and heart failure in COPD patients -blockers are unequivocally
beneficial in treating CVD and heart failure Meta-analysis
demonstrated that -blockers are well tolerated in mild to moderate
COPD -blockers commonly withheld from COPD patients
Slide 28
IV. Evaluation of Literature: Objectives Evaluate two primary
studies dealing with the use of - blockers in the COPD patient
population Both studies designed to: Determine whether -blockers
can reduce the number of COPD exacerbations Determine if -blockers
can decrease all-cause mortality in COPD patients
Slide 29
IV. Benefit of -blockers in COPD: Study from Archives of Intern
Med -blockers may reduce mortality and risk of exacerbations in
patients with chronic obstructive pulmonary disease. Arch Intern
Med. Rutten et al. 2010. Utrecht general practitioners network
database, Utrecth, Netherlands Jan 1992Dec 2005 n=2,230 Purpose of
study: Determine whether long-term -blocker use improves outcomes
for patients with COPD
Slide 30
IV. Study 1 Methods and Design Observational cohort study One
group of patients followed over extended period of time All
information was gathered from Utrecht general practitioners network
database Network database included information related to: Disease
status Reasons for encounter Specialist letters Prescription use
All patient related information gathered between Jan 1992 and Dec
2005 The database included the information of over 60,000
patients
Slide 31
IV. Study 1 Inclusion Criteria Inclusion Criteria: Over the age
of 45 Diagnosis of COPD during study period -blocker usage during
study period (Dec 1992Jan 2010) 2,230 of 60,000 patients met these
criteria and were included in the study
Slide 32
IV. Study 1 Outcome Variables The two primary outcomes for the
study were: COPD exacerbations within the study time frame
All-cause mortality Patients were followed until death or until the
end of the study period Patients who had a COPD exacerbation were
still eligible for the study outcome of death
Slide 33
IV. Study 1 Statistical Methods Hazard ratios (HRs) and
confidence intervals (CIs) were calculated using Cox proportional
hazards regression analyses Cox proportional hazards regression
analyses is appropriate for observational cohort studies Adjusted
HRs calculated after correction for the following variables: Age
Gender Current and former smoking status History of cardiovascular
disease Hypertension Diabetes mellitus Cardiovascular drug use
besides -blocker Pulmonary drug use
Slide 34
IV. Study 1 Statistical Methods Sub-group analyses performed to
correct for confounding variables Sub-group analyses were performed
on patients who: Did not have overt cardiovascular disease Used two
or more pulmonary drugs Used inhaled -agonists Used inhaled
anticholinergic agents Were referred to a pulmonologist
Slide 35
IV. Study 1 Results: Hazard Ratios for Mortality According to
-blocker Use VariableAny -blocker (95% CI) Cardioselective -blocker
(95% CI) Nonselective - blocker (95% CI) Unadjusted hazard ratios
0.70 (0.59-0.84)0.69 (0.57-0.83)*0.80 (0.61-1.06) Adjusted hazard
ratios 0.64 (0.52-0.77)0.63 (0.51-0.77)*0.80 (0.60-1.05)
Slide 36
IV. Study 1 Results: Hazard Ratios for Mortality According to
-blocker Use in Subgroups of Patients VariableUnadjusted hazard
ratio (95% CI) any - blocker Adjusted hazard ratio (95% CI) any -
blocker No overt cardiovascular disease (n=1229) 0.60
(0.41-0.87)0.67 (0.45-0.99) Patients who used 2 or more pulmonary
drugs (n=1419) 0.66 (0.53-0.82)0.62 (0.53-0.82) Patients who
inhaled -agonists (n=1288) 0.66 (0.52-0.83)0.64 (0.49-0.85)
Patients who inhaled anticholinergic agents (n=1357) 0.68
(0.56-0.84)0.68 (0.53-0.87)
Slide 37
IV. Study 1 Results: Hazard Ratios for COPD Exacerbations
According to -blocker Use VariableAny -blocker (95% CI)
Cardioselective -blocker (95% CI) Nonselective - blocker (95% CI)
Unadjusted hazard ratios 0.73 (0.63-0.83)0.75 (0.65-0.87)0.72
(0.57-0.90) Adjusted hazard ratios 0.64 (0.55-0.75)0.68
(0.58-0.80)0.70 (0.56-0.89)
Slide 38
IV. Study 1 Results: Hazard Ratios for COPD Exacerbations
According to -blocker Use in Subgroups of Patients
VariableUnadjusted hazard ratio (95% CI) any -blocker Adjusted
hazard ratio (95% CI) any -blocker No overt cardiovascular disease
(n=1229) 0.66 (0.53-0.84)0.66 (0.52-0.86) Patients who used 2 or
more pulmonary drugs (n=1419) 0.76 (0.65-0.88)0.72(0.60-0.86)
Patients who used inhaled -agonists (n=1288) 0.78 (0.66-0.91)0.71
(0.59-0.86) Patients who used inhaled anticholinergic agents
(n=1357) 0.73 (0.62-0.85)0.71 (0.59-0.85)
Slide 39
IV. Study 1 Strengths and Weaknesses StrengthsWeaknesses Large
patient population Long follow-up period (1992-2005) Sub-group
analyses performed to address confounding variables Observational
study, not double- blind or placebo controlled COPD diagnosis
methods were not uniform Authors speculated that about 70% of cases
conformed to the GOLD diagnosis guidelines Practitioners did not
always use spirometry to diagnose COPD in their patients. Severity
of COPD not always known
Slide 40
IV. Study 1 Conclusions Authors conclusions: -blockers may
reduce all-cause mortality and disease exacerbations in a wide
range of COPD patients My conclusions: Cardioselective -blockers
may be beneficial in reducing mortality and morbidity in COPD
patients 95% CI for non-cardioselective -blockers included values
> 1
Slide 41
IV. Benefit of -blockers in COPD: Study from BMJ Effect of
blockers in treatment of chronic obstructive pulmonary disease: a
retrospective cohort study. BMJ. Short et al. 2011. Tayside
respiratory disease information system, Tayside, Scotland Jan
2001Jan 2010 n=5,977
Slide 42
IV. Study 2 Purpose Assess the use of -blockers in management
of COPD and determine their effect on: Mortality Hospital
admissions COPD exacerbations Outcomes were measured after being
stratified according to stepwise treatment of COPD
Slide 43
IV. Study 2 Methods and Design Observational cohort study One
group of patients followed over extended period of time Researchers
gathered disease information from the Tayside respiratory disease
information system (TARDIS) of Tayside, Scotland Data within TARDIS
includes: Patient demographics Respiratory symptoms Lung function
(spirometry data) Smoking history Entry into the TARDIS system
requires that a diagnosis of COPD is based on GOLD guidelines
Slide 44
IV. Study 2 Inclusion Criteria Inclusion Criteria: Live in the
Tayside, Scotland area 50 years old Diagnosis of COPD between Jan
2001Jan 2010 5977 individuals met these criteria and were included
in the study
Slide 45
IV. Study 2 Outcome Variables Outcome variables included: All
cause mortality Emergency oral corticosteroid use
Respiratory-related hospital admissions Patients were followed
until death or the end of the study period
Slide 46
Study 2 Statistical Methods Patients were divided into
subgroups based upon their maximal stepwise inhaled treatment and
-blocker use Different from Arch Inter Med study in that
participants were stratified according to COPD treatment
regimens
Slide 47
IV. Study 2 Statistical Methods Crude and adjusted hazard
ratios were calculated for each of the following: All cause
mortality Hospital admissions due to respiratory disease Emergency
oral corticosteroid use All hazard ratios were calculated using Cox
proportional hazard regression analysis
Slide 48
IV. Study 2 Statistical Methods Adjusted hazard ratios for
mortality were calculated after correcting for the following
covariates: Cardiovascular and respiratory hospital admissions
Diabetes Smoking Age at diagnosis Gender Cardiac drug use FEV 1
Resting SaO 2 deprivation index
Slide 49
IV. Study 2 Results: Risk of All- Cause Mortality Treatment
Groups Treatment groupsAdjusted hazard ratios (95% CI) ICS0.69
(0.58 to 0.83) ICS+BB0.48 (0.31 to 0.74) ICS+LABA0.64 (0.57 to
0.74) ICS+LABA+BB0.44 (0.31 to 0.62) ICS+LABA+Tio0.43 (0.38 to
0.48) ICS+LABA+Tio+BB0.28 (0.21 to 0.39) LABA or Tio (no ICS)0.71
(0.59 to 0.84) LABA or Tio (no ICS)+BB0.52 (0.36 to 0.76) BB (no
ICS)0.65 (0.51 to 0.83) ICS +Tio0.61 (0.47 to 0.80)
Slide 50
IV. Study 2 Results: Risk of Emergency Oral Corticosteroid
Prescription Treatment groupsAdjusted hazard ratios (95% CI)
ICS*0.77 (0.69 to 0.87) ICS+BB*0.51 (0.39 to 0.69) ICS+LABA0.93
(0.85 to 1.03) ICS+LABA+BB0.46 (0.34 to 0.63) ICS+LABA+Tio0.68
(0.61 to 0.75) ICS+LABA+Tio+BB0.31 (0.22 to 0.43) LABA or Tio (no
ICS)*0.67 (0.59 to 0.76) LABA or Tio (no ICS)+BB*0.44 (0.33 to
0.59) BB (no ICS)0.39 (0.32 to 0.48) ICS +Tio0.81 (0.68 to
0.96)
Slide 51
IV. Study 2 Results: Risk of Hospital Admission Treatment
groupsAdjusted hazard ratios (95% CI) ICS0.79 (0.66 to 0.95)
ICS+BB0.36 (0.22 to 0.58) ICS+LABA0.82 (0.70 to 0.96)
ICS+LABA+BB0.39 (0.26 to 0.60) ICS+LABA+Tio0.70 (0.61 to 0.80)
ICS+LABA+Tio+BB0.32 (0.22 to 0.44) LABA or Tio (no ICS)0.70 (0.58
to 0.85) LABA or Tio (no ICS)+BB0.31 (0.19 to 0.51) BB (no ICS)0.31
(0.22 to 0.44) ICS +Tio0.71 (0.53 to 0.96)
Slide 52
IV. Study 2 Strength and Weaknesses StrengthsWeaknesses Large
patient population Long follow-up period Stratified according to
concurrent COPD drug treatments All patients diagnosed using the
GOLD diagnosis guideline criteria Smoking status and history known
for all patients Observational study, not double-blind or placebo
controlled The specific indication was not known for all
prescriptions of -blockers Researchers used a cut-off age of 50
years (previous COPD observational studies used a cut-off age of 45
years)
Slide 53
IV. Study 2 Conclusions Authors conclusions: -blockers, when
added to stepwise COPD treatment, may reduce mortality and
morbidity independent of overt cardiovascular disease My
conclusions: -blockers may reduce morbidity in the COPD patient
population when added to stepwise therapy, but the effect on
mortality is uncertain 95% CIs for treatment and non-treatment
groups overlapped
Slide 54
IV. Evaluation of Literature: Summary Cardioselective
-blockers, when added to stepwise COPD therapy, may reduce disease
exacerbations Both studies showed a significant reduction in the
risk of COPD exacerbations The effect of -blockers on reducing
mortality in COPD patients is still uncertain Both studies
identified a trend in reducing the risk of mortality
Slide 55
Summary of Presentation Section I. COPD etiology and
pathophysiology Differences between asthma and COPD Diagnosis of
COPD Section II. COPD pharmacotherapeutic options Importance of
vaccination in COPD Section III. Prevalence of CVD and heart
failure in COPD patients Relative safety of -blockers in the COPD
population Avoidance of -blocker use in the COPD population Section
IV. Cardioselective -blockers may reduce morbidity and mortality in
COPD patients
Slide 56
V. Expert Consensus: -blocker use in COPD Patients KMC
pulmonologists recommendations: In absence of bronchospasm,
-blocker use in COPD patients is appropriate Preferentially use
cardioselective agents Start at lower doses and titrate to desired
effect Monitor heart rate, blood pressure, etc. Be aware of
potential adverse effects Risk of acute bronchospasm Increased
airway hyper-responsiveness Possible inhibition of bronchodilator
response
Slide 57
V. My Recommendations Data is adequate to encourage the use of
-blockers in patients with mild to moderate COPD Cardioselective
-blockers should not be withheld from COPD patients because of
concerns about side- effects Patients should, however, continue to
receive education on the potential side-effects of -blockers
Prescribers should be aware of the potential benefit of adding
-blockers in management of COPD patients with CVD
comorbidities
Slide 58
Questions?
Slide 59
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