Seth Haslam, PharmD Candidate 2012 Idaho State University College of Pharmacy.

Seth Haslam, PharmD Candidate 2012 Idaho State University College of Pharmacy

Personal Disclaimer I claim no financial interests or relationships which would influence the body of my presentation

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

III. -receptor Pharmacology: Review Cardiac muscle Increased inotropy and chronotropy Bronchial smooth muscle Bronchodilation

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)

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

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

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

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

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

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

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

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

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

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

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

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)

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)

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)

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)

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

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

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

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

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

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

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

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

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

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

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)

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)

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)

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)

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

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

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

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

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

Questions?

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Seth Haslam, PharmD Candidate 2012 Idaho State University College of Pharmacy.

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Transcript of Seth Haslam, PharmD Candidate 2012 Idaho State University College of Pharmacy.