asthma/copd update -...

Asthma/COPD Update with Inhaler Workshop

October 8, 2017

Nathan Samsa, DO, Pharm D, RPh, FACOI

Disclosures

• None

Agenda

• Asthma Updates

• COPD Updates

• Inhaler Workshop

Medication Acronyms

• SABA: Short acting beta agonist

• LABA: Long acting beta agonist

• LAMA: Long acting muscarinic antagonist

• ICS: Inhaled corticosteroid

Asthma Updates

Asthma Updates

• SMART Trial aftermath

• Guidelines (GINA, ERS/ATS)

• FeNO testing

• Biologics

SMART Trial

• 2006: The Salmeterol Multicenter Asthma Research Trial

• Compared salmeterol vs. placebo added to usual care

• Subjects:

• 26,355 patients

• >12 years of age

Nelson HS, Weiss ST, Bleeker ER, et al. The Salmeterol Multicenter Research Trial: A Comparison of Usual Pharmacotherapy for Asthma or Usual Pharmacotherapy Plus Salmeterol. Chest. 2016. 129: 15-26.

SMART Findings

• No significant difference between the two for:

• Overall safety

• Respiratory-related deaths (50 vs 36)

• Life-threatening experiences

• HOWEVER………………

Nelson HS, Weiss ST, Bleeker ER, et al. The Salmeterol Multicenter Research Trial: A Comparison of Usual Pharmacotherapy for Asthma or Usual Pharmacotherapy Plus Salmeterol. Chest. 2016. 129: 15-26.

Salmeterol Is Evil

• Small increase in respiratory-related deaths (24 vs 11)

• Small increase in asthma-related deaths (13 vs 3)

• Majority were in African-Americans (20 vs 5)

• All were statistically significant

• So based on 15 more patients deaths with salmeterol from this subset population…

Nelson HS, Weiss ST, Bleeker ER, et al. The Salmeterol Multicenter Research Trial: A Comparison of Usual Pharmacotherapy for Asthma or Usual Pharmacotherapy Plus Salmeterol. Chest. 2016. 129: 15-26.

Innocent Bystanders

BELT Trial

• Evaluated tiotropium vs. LABA in addition to inhaled corticosteroids (ICS) in black population over 18 months

• Tiotropium + ICS (n = 532)

• LABA + ICS (n = 538)

Weschler ME, Yawn BP, Fuhlbrigge AL, et al. Anticholinergic vs Long-Acting β-Agonist in Combination With Inhaled Corticosteroids in Black Adults With Asthma. JAMA. October 27, 2015. 314(16): 1720-1730.

BELT Findings

• No difference in clinical outcomes, including FEV1

• No significant difference with non-asthma and asthma-related adverse effects (P = 0.16)

• 3 deaths occurred, all in tiotropium group

Weschler ME, Yawn BP, Fuhlbrigge AL, et al. Anticholinergic vs Long-Acting β-Agonist in Combination With Inhaled Corticosteroids in Black Adults With Asthma. JAMA. October 27, 2015. 314(16): 1720-1730.

AUSTRI Trial

• Evaluated safety of adding salmeterol to fluticasone in adults and adolescents (ages ≥12)

• Fluticasone only (n = 5834)

• Black (n = 856; 15%)

• Fluticasone + salmeterol (n = 5845)

• Black (n = 870; 15%)

Stempel DA, Raphiou IH, Kral KM, et al. Serious Asthma Events with Fluticasone plus Salmeterol versus Fluticasone Alone. NEJM. May 12, 2016. 374: 1822-1830.

AUSTRI Findings

• Asthma exacerbations

• Fluticasone only (n = 597)

• Fluticasone + salmeterol (n = 480)

• Adding salmeterol reduced exacerbations 16-32%

• Asthma exacerbations in black patients

• Fluticasone only (n = 79)

• Fluticasone + salmeterol (n = 79)

Stempel DA, Szefler SJ, Pederson S, et al. Safety of Adding Salmeterol to Fluticasone Propionate in Children with Asthma. NEJM. September 1, 2016. 375: 840-849.

VESTRI Trial

• Evaluated safety of adding salmeterol to fluticasone in children (ages 4-11)

• Fluticasone only (n = 3101)

• Black (n = 511; 16.5%)

• Fluticasone + salmeterol (n = 3107)

• Black (n = 539; 17.3%)

Stempel DA, Raphiou IH, Kral KM, et al. Serious Asthma Events with Fluticasone plus Salmeterol versus Fluticasone Alone. NEJM. May 12, 2016. 374: 1822-1830.

VESTRI Findings

• Asthma exacerbations

• Fluticasone only (n = 309)

• Fluticasone + salmeterol (n = 265)

• Asthma exacerbations in black patients

• Fluticasone only (n = 21)

• Fluticasone + salmeterol (n = 27)

Stempel DA, Szefler SJ, Pederson S, et al. Safety of Adding Salmeterol to Fluticasone Propionate in Children with Asthma. NEJM. September 1, 2016. 375: 840-849.

VESTRI Findings

• Serious asthma-related events

• Fluticasone only (n = 21)

• Fluticasone + salmeterol (n = 27)

• No deaths!

• Salmeterol + fluticasone is non-inferior to fluticasone alone

• Correlates to AUSTRI findings in children

Stempel DA, Szefler SJ, Pederson S, et al. Safety of Adding Salmeterol to Fluticasone Propionate in Children with Asthma. NEJM. September 1, 2016. 375: 840-849.

Is There A Class Effect?

• Salmeterol vindicated? What about formoterol?

• NEJM 9/1/2016: Evaluated safety of adding formoterol to budesonide (ages ≥12)

• Fluticasone only (n = 5766)

• Black (n = 407; 6.9%)

• Fluticasone + salmeterol (n = 5785)

• Black (n = 396; 6.8%)

Peters SP, Bleeker ER, Canonica GW, et al. Serious Asthma Events with Budesonide plus Formoterol vs. Budesonide Alone. NEJM. September 1, 2016. 375: 850-860.

Study Findings

• Risk of asthma exacerbation

• Budesonide only (n = 633, 10.8%)

• Budesonide + formoterol (n = 539, 9.2%)

• Asthma-related deaths

• Budesonide only (n = 0)

• Budesonide + formoterol (n =2, <0.1%)

Peters SP, Bleeker ER, Canonica GW, et al. Serious Asthma Events with Budesonide plus Formoterol vs. Budesonide Alone. NEJM. September 1, 2016. 375: 850-860.

Overall Findings

• No evidence that LABA on top of inhaled corticosteroid increases risk of asthma-related death

• No data on lone LABA compared to ICA or ICA + LABA

GINA 2017

GINA Stepwise Approach

GINA ICS

NAEPP Guidelines

• National Asthma Education and Prevention Program: Expert panel report III. 2007

Classification Mild

intermittent Mild persistent Moderate persistent Severe

persistent

Symptoms ≤2d/wk >2d/wk, not QD QD QD multiple times

Nighttime awakenings ≤2x/mo 3-4x/mo >1x/wk, not nightly QD

SABA use ≤2d/wk >2d/wk, not QD, not >1x/d

QD QD multiple times

Limitation None Mild Moderate Severe

FEV1 >80% >80% 60-80% <60%

ICD-10

• Classification: • Mild intermittent asthma: J45.2x

• Mild persistent asthma: J45.3x

• Moderate persistent asthma: J45.4x

• Severe persistent asthma: J45.5x

• Unspecified asthma: J45.90x

• Severity (x) • Uncomplicated: 0

• Exacerbation: 1

• Status asthmaticus: 2

FeNO

• Fractional concentration of exhaled nitric oxide

• Modestly associated with eosinophilic airway inflammation

• Can be seen in other eosinophilic states w/o asthma

• Not elevated in neutrophilic asthma phenotype

• Decreased in smokers

• Does not help rule in or out asthma

FeNO cont.

• Recommended neither by GINA nor ERS/ATS

• ERS/ATS 2014: “We suggest that clinicians do not use FeNO in addition to clinical criteria to guide therapy in adults or children with severe asthma (conditional recommendation, very low quality evidence).1

• GINA 2017: “At present, neither sputum- nor FENO-guided treatment is recommended for the general asthma population.” (Evidence A)2

1. Chung KF, Wenzel SE, Brozek JL et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J. 2014. 43: 343-373.

2. 2. Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention, 2017. Available from: www.ginasthma.org

FeNO Interpretation: ICS Naïve

FeNO Interpretation: On ICS

Biologics In Asthma

• Omalizumab (Xolair®)

• Mepolizumab (Nucala®)

• Reslizumab (Cinqair®)

Omalizumab

• Anti-IgE antibody

• For patients who failed ICS

• Baseline IgE 30-700 IU/mL

• Limited information in treatment >700 IU/mL

• Note: 1 IU/mL = 2.5ng/mL

Omalizumab cont.

• Goal is to reduce IgE <10 IU/mL

• Cannot use IgE levels to monitor; levels increase due to IgE-anti-IgE complexes

• May take up to 1 year for IgE levels to decrease

• Issues:

• Anaphylaxis

• Questionable increased cancer risk

• Developed soon after starting therapy – pre-existing?

Mepolizumab, Reslizumab

• Interleukin-5 (IL-5) antibody

• IL-5 responsible for differentiation and growth of eosinophils

• Mepolizumab

• Eosinophil count ≥150 cells/μL within 6 weeks of therapy

• Eosinophil count ≥300 cells/μL within past 12 months

• Reslizumab

• Eosinophil count ≥400 cells/μL

COPD Updates

COPD Updates

• GOLD 2017

• Azithromycin in COPD

• Asthma-COPD overlap syndrome

GOLD 2017

GOLD Scales

GOLD ABCD

GOLD Treatment Algorithm

Azithromycin In COPD

• Macrolides have anti-inflammatory properties

• Evaluated number of exacerbations of azithromycin 250mg daily vs placebo (n = 1577)

• Placebo: 1.83 exacerbations/year

• Azithromycin: 1.48 exacerbations/year

• P = 0.01

• Concern about QTc prolongation/cardiac issues

Albert RK, Connett J, Baily WC, et al. Azithromycin for Prevention of Exacerbations of COPD. NEJM. August 25, 2011. 365(8): 689-698.

Azithromycin & Cardiac Risk

• Cohort evaluated 3,546,239 patients between those who took:

• No antibiotics (n = 1,391,180)

• Amoxicillin (n = 1,348,672)

• Azithromycin (n = 347,795); over 5 days

• Ciprofloxacin (n = 246,626)

• Levofloxacin (n = 193,906)

Ray WA, Murray KT, Hall K, et al. Azithromycin and the Risk of Cardiovascular Death. NEJM. May 17, 2012. 366(20): 1881-1890.

Azithromycin & Cardiac Risk cont.

• Small increased risk of cardiovascular death with azithromycin (not significantly different from levofloxacin, but significantly greater than ciprofloxacin)

• Most pronounced in patients with underlying cardiovascular disease

Ray WA, Murray KT, Hall K, et al. Azithromycin and the Risk of Cardiovascular Death. NEJM. May 17, 2012. 366(20): 1881-1890.

Does Azithromycin Increase Risk?

• Different cohort from Denmark evaluated 2,204,469 azithromycin prescriptions compared to no antibiotic use and penicillin V

• No increased risk of cardiovascular death with azithromycin compared to penicillin

• In fact, penicillin had more cardiac deaths (146 vs. 17) and azithromycin had a -1 adjusted absolute risk of cardiac death

Asthma-COPD Overlap

• Continuum of obstructive diseases, not just separate entities

• Features of both COPD and asthma

• Asthma can have negative bronchodilator response

• COPD can have positive bronchodilator response

• Not defined by GINA or GOLD

• Multiple definitions by other organizations

Postma DS and Rabe KF. The Asthma-COPD Overlap Syndrome. NEJM. September 24, 2015. 373(13): 1241-1249.

One Attempt At Diagnosis

Sin DD, Miravitlles M, Mannino D, et al. What is asthma-COPD overlap syndrome? Towards a consensus statement from a round table discussion. Eur Respir J. 2016. 48: 664-673.

“The Five Commandments”

• 1) “A patient with asthma may develop non-fully reversible airflow obstruction but this is not COPD, not even ACO; it is obstructive asthma.”

• 2) “A patient with asthma who smokes may also develop non-fully reversible airflow obstruction, which differs from obstructive asthma and from ‘pure’ COPD. This is the most frequent type of patient with ACO.”

Miravitlles M. Diagnosis of asthma-COPD overlap: the five commandments. Eur Respir J. 2017. 49: 1700506.

“The Five Commandments”

• 3) “Some patients who smoke and develop COPD may have a genetic Th2 background (even in the absence of a previous history of asthma) and can be identified by high eosinophil counts in peripheral blood. These individuals could be included under the umbrella term of ACO.”

Miravitlles M. Diagnosis of asthma-COPD overlap: the five commandments. Eur Respir J. 2017. 49: 1700506.

“The Five Commandments”

• 4) “A patient with COPD and a positive bronchodilator test (>200 mL and >12% FEV1 change) has reversible COPD but is not an asthmatic, or even ACO.”

• 5) “A patient with COPD and a very positive bronchodilator test (>400 mL FEV1 change) is more likely to have some features of asthma and could also be classified as ACO.”

Miravitlles M. Diagnosis of asthma-COPD overlap: the five commandments. Eur Respir J. 2017. 49: 1700506.

Inhaler Workshop

Inhaler Workshop

• Review currently available inhaled medications

• Discuss factors when selecting inhaled medication

• Critique currently available delivery devices

• Hands-on session

Inhaled Medications

• Beta (β2) agonists

• Short acting

• Long acting

• Muscarnic (M3) antagonists

• Short acting

• Long acting

• Inhaled corticosteroids

• LAMA

• Tiotropium (Spiriva®)

• HandiHaler®: 9/24/04

• Respimat®: 9/24/14

• Aclidinium (Tudorza®): 7/23/12

• Umeclidinium (Incruse®): 4/30/14

• Glycopyrrolate (Seebri®): 10/29/15

• LABA

• Salmeterol (Serevent®): 9/19/97

• Arformoterol (Brovana®): 10/6/06

• Formoterol (Perforomist®): 5/11/07

• Indacaterol (Arcapta®): 7/1/11

• Olodaterol (Striverdi®): 7/31/14

• ICS

• Mometasone (Asmanex®)

• Twisthaler®: 3/30/05

• HFA: 4/25/14

• Fluticasone Propionate (Flovent®)

• Diskus®: 9/29/00

• HFA: 5/14/04

• Flunisolide (Aerospan®) 1/27/06

• Budesonide (Pulmicort®)

• Respules®: 8/8/00

• Flexhaler®: 7/12/06

• Ciclesonide (Alvesco®): 1/10/08

• Beclomethasone (Qvar®)

• HFA: 9//15/00

• RediHaler®: 8/3/17

• Fluticaonse Furoate (Arnuity®): 8/20/14

• LABA/ICS

• Salmeterol/Fluticasone Propionate (Advair®)

• Diskus®: 8/24/00

• HFA: 6/8/06

• Formoterol/Budesonide (Symbicort®): 7/21/06

• Formoterol/Mometasone (Dulera®): 6/22/10

• Vilanterol/Fluticasone Furorate (Breo®): 5/10/13

• LABA/LAMA

• Vilanterol/Umeclidinium (Anoro®): 12/18/13

• Olodaterol/Tiotropium (Stiolto®): 5/21/15

• Indacaterol/Glycopyrrolate (Utibron®): 10/29/15

• Formoterol/Glycopyrrolate (Bevesepi®): 4/25/16

• LABA/LAMA/ICS

• Vilanterol/Umeclidinium/Fluticasone Furorate (Trelegy®): 9/18/17

• Discontinued inhalers

• Metaproterenol (Alupent®): 6/14/10

• Triamcinolone (Azmacort®): 12/31/10

• Pirbuterol (Maxair®): 12/31/13

• Formoterol (Foradil®): 12/31/15

• Nedocromil (Tilade®): 6/14/10

• Cromolyn (Intal®): 12/31/10

Goals for Inhalation

• Deliver drug to respiratory mucosa

• Minimize systemic absorption

Factors Affecting Delivery

• Drug/formulation-related

• Device-related

• Patient/disease-related

Thorrson, L and Geller D. Factors guiding the choice of delivery device for inhaled corticosteroids in the long-term management of stable asthma and COPD: Focus on budesonide. Resp Med. July, 2005. 99(7); 836-849.

Drug/Formulation Issues

• Drug potency

• Pharmacokinetics

• Particle size

• Propellant

• Additives

• Viscosity

Thorrson, L and Geller D. Factors guiding the choice of delivery device for inhaled corticosteroids in the long-term management of stable asthma and COPD: Focus on budesonide. Resp Med. July, 2005. 99(7): 836-849.

Device Issues

• Deposition properties

• Particle size

• Ease of use

• Accuracy of dosage

• Administration apparatus

Thorrson, L and Geller D. Factors guiding the choice of delivery device for inhaled corticosteroids in the long-term management of stable asthma and COPD: Focus on budesonide. Resp Med. July, 2005. 99(7): 836-849.

Patient/Disease Issues

• Inspiratory flow rate

• Upper airway anatomy

• Lower airway obstruction

• Ability to use device

• Competency

• Cost

• Patient preference & adherence Thorrson, L and Geller D. Factors guiding the choice of delivery device for inhaled corticosteroids in the long-term management of stable asthma and COPD: Focus on budesonide. Resp Med. July, 2005. 99(7): 836-849.

Remember This?

Chlorofluorocarbons (CFCs)

• Used as propellants in aerosols

• Also refrigerants and solvents

• Destroyed ozone layer

• Montreal Protocol on Substances that Deplete the Ozone Layer

• September 16, 1987

• Phase out CFCs

Inhalers: Ozone Killers!

• FDA phased out generic albuterol as of 12/31/2008

• Newer albuterol products use hydrofluoroalkane (HFA)

• Available then as now:

• ProAir HFA

• Proventil HFA

• Ventolin HFA

• $$$ and still no generics…

https://www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ucm063054.htm Accessed October 2, 2017

The Only Good Casualty

Delivery Systems

• Diskus®

• Ellipta®

• Flexhaler®

• HandiHaler®

• NeoHaler®

• Pressair®

• RespiClick®

• Respimat®

• HFA

• Nebulizer

Diskus®

• Flovent®

• Fluticasone propionate

• Serevent®

• Salmeterol

• Advair®

• Fluticasone propionate + Salmeterol

Ellipta®

• Arnuity® • Fluticasone furoate

• Incruse® • Umeclidinium

• Anoro® • Umeclidinium + Vilanterol

• Breo® • Fluticasone furoate + Vilanterol

• Trelegy® • Fluticasone furoate + Vilanterol + Umeclidinium

Flexhaler®

• Pulmicort®

• Budesonide

HandiHaler®

• Spiriva®

• Tiotropium

NeoHaler®

• Arcapta®

• Indacaterol

• Seebri®

• Glycopyrrolate

• Utibron®

• Indacaterol + Glycopyrrolate

Pressair®

• Tudorza®

• Aclidinium

RespiClick®

• ProAir®

• Albuterol

Respimat®

• Spiriva®

• Tiotropium

• Striverdi®

• Olodaterol

• Stiolto®

• Tiotropium + Olodaterol

• Combivent®

• Albuterol + Ipratropium

HFA

• ProAir®

• Albuterol

• Proventil®

• Albuterol

• Ventolin®

• Albuterol

• Xopenex®

• Levalbuterol

Nebulizer

• Albuterol

• Ipratropium

• DuoNeb®

• Albuterol + Ipratropium

• Brovana®

• Arformoterol

• Perforomist®

• Formoterol

• Pulmicort Respules®

• Budesonide

Device Selection Summary

• Chose drug(s)

• Based on GINA/GOLD guidelines

• Clinical history

• Dosing regimen

• Chose delivery system

• Is patient able to use it physically?

• Mental competence?

• Is it covered by insurance?

Why Care About Teaching?

• You can get paid for it!

• CPT: 94664

• Document!

• My example: “I personally instructed the patient on the use of [Inhaler Name]. Appropriate technique was demonstrated. Questions answered. Sample provided to patient.”

The End

Thank you for your time!