Asthma Upate 2018: What s New Since the 2007 Asthma Guidelines of NAEPP?

Transcription

1 10:50-11:50am Asthma Update 2018: What s New Since the 2007 National Asthma Guidelines? SPEAKER Christopher H. Fanta, MD Disclosures The following relationships exist related to this presentation: Christopher H. Fanta, MD: No financial disclosures Off-Label/Investigational Discussion In accordance with pmicme policy, faculty have been asked to disclose discussion of unlabeled or unapproved use(s) of drugs or devices during the course of their presentations. Asthma Upate 2018: What s New Since the 2007 Asthma Guidelines of NAEPP? Christopher H. Fanta, M.D. Partners Asthma Center Pulmonary and Critical Care Medicine Division Brigham and Women s Hospital Harvard Medical School Conflicts of Interest None.

2 Outline Sources of Nitric Oxide in Exhaled Breath Measurement of exhaled nitric oxide Safety of long acting beta agonists Anticholinergic bronchodilators (LAMAs) New medication delivery devices Biologics in severe asthma Airway epithelial cells Increased in airway inflammation Eosinophils Exhaled NO as a surrogate biomarker for eosinophilia/th2 inflammation Evolution of Equipment to Measure Exhaled NO Cut Off Values for FE NO + NiOx NiOx Mino NiOx Vero Dweik RA, et al. An Official ATS Clinical Practice Guideline. AJRCCM 2011; 184:

3 Cut Off Values for FE NO Normal: <25 ppb Indeterminate: ppb High: >50 ppb Potential Utility Detect eosinophilic airway inflammation; Monitor airway inflammation to determine potential need for adjusting corticosteroids; Unmask unsuspected non adherence to corticosteroids. Dweik RA, et al. An Official ATS Clinical Practice Guideline. AJRCCM 2011; 184: Dweik RA, et al. An Official ATS Clinical Practice Guideline. AJRCCM 2011; 184: Case Example: Case Example #1 (cont.) 58 year old radiologist with persistent cough for 3 weeks. History of mild intermittent wheezing for last 8 years, worse when returning home to Cambridge at the end of the summer. 3 cats and a dog at home. Other history: oral allergy syndrome; no sensitivity to the cold. Normal exam, clear including chest exam. Spirometry with borderline mild airflow obstruction.

4 Case Example #1 (cont.) Normal exam, clear including chest exam. Spirometry with borderline mild airflow obstruction. Exhaled nitric oxide = 202 ppb. Clinical Practice Summary from American Thoracic Society a quantitative, noninvasive, simple, and safe method of measuring airway inflammation that provides a complementary tool to other ways of assessing airways disease, including asthma. Dweik RA, et al. An Official ATS Clinical Practice Guideline. AJRCCM 2011; 184: Outline NAEPP Guidelines 2007: Step 3 (Moderate Persistent Asthma) Measurement of exhaled nitric oxide Safety of long acting beta agonists Anticholinergic bronchodilators (LAMAs) New medication delivery devices Biologics in severe asthma Equal weight given to two therapeutic options: Add long acting beta agonist (LABA) to low dose of inhaled corticosteroid (ICS) or Increase the dose to ICS to medium dose range

5 Adding Salmeterol vs. Increasing the Dose of Inhaled Corticosteroids 426 patients at 99 general practitioner centers Symptomatic despite beclomethasone dipropionate (BDP) 400 g/day Randomized to: BDP 400 g/day plus salmeterol 50 g BID vs. BDP 1000 g/day Double blind, double dummy 6 month trial Greening et al., Lancet 1994;344:219. Change in PEF (L/min) LABA/ICS vs ICS Alone in Moderate Asthma: Peak Flow Mean Morning PEF Salmeterol +BDP High dose BDP Weeks of Treatment Greening et al., Lancet 1994; 344:291 Safety Concerns Regarding Long Acting Inhaled Beta Agonists Black Box warning regarding salmeterol: WARNING: DATA FROM A LARGE PLACEBO CONTROLLED US STUDY THAT COMPARED THE SAFETY OF SALMETEROL (SEREVENT INHALATION AEROSOL) OR PLACEBO ADDED TO USUAL ASTHMA THERAPY SHOWED A SMALL BUT SIGNIFICANT INCREASE IN ASTHMA RELATED DEATHS IN PATIENTS RECEIVING SALMETEROL (13 DEATHS OUT OF 13,176 PATIENTS TREATED FOR 28 WEEKS) VERSUS THOSE ON PLACEBO (3 OF 13,179) (SEE WARNINGS AND CLINICAL TRIALS: ASTHMA: SALMETEROL MULTI CENTER ASTHMA RESEARCH TRIAL). Salmeterol Multicenter Asthma Research Trial (SMART) 26,000 subjects (of planned 60,000) randomized to salmeterol vs placebo plus usual care for 6 months Outcomes: respiratory/asthma deaths and near deaths (respiratory failure) Nelson et al., Chest 2006; 129:15 26.

6 SMART: Study Design Usual Care + blinded salmeterol MDI BID Salmeterol Multicenter Asthma Research Trial (SMART) No LABA >12 years old No β blockers R Phone contact every 4 weeks Usual Care + blinded placebo MDI BID Findings at time of study termination: more asthma deaths (13 vs. 3) and more lifethreatening or fatal asthma events (37 vs. 22) in the salmeterol treated group. Study Visit 1 Day 0 Nelson et al., Chest 2006; 129: weeks Subgroups at particular risk: African Americans those not on inhaled steroids Salmeterol Multicenter Asthma Research Trial (SMART) LABAs and Fatal Asthma: Other Potential Explanations The data from SMART are not adequate to determine whether concurrent use of inhaled corticosteroids provides protection from the risk of serious outcomes. Genetic variation in our beta receptors Blockade of action of quick acting betaagonist bronchodilator GlaxoSmithKline in collaboration with the FDA Unknown pharmacologic mechanism

7 FDA Drug Safety Communication (February, 2010) Long acting inhaled beta agonists (LABAs): Should not be used long term in patients whose asthma can be controlled on an anti inflammatory controller alone; Should be used for as short a period of time as needed to achieve control, then stopped in favor of anti inflammatory controller alone. FDA Mandated Trials on the Safety of Inhaled LABAs 4 placebo controlled RCTs of ICS + LABA vs. ICS alone in adults (N = 11,700 each) and 1 in children 4 11 years (N = 6,200) Primary end point: composite of hospitalization, intubation, and asthma related deaths 90% power to detect doubling of relative risk Begun in 2011, results in 2017 Chowdhury BS, et al, NEJM 2011; 364:2473. Fluticasone + Salmeterol vs. Fluticasone alone Among 11,679 patients randomized to fluticasone (in 3 doses) vs. fluticasone (3 doses) plus salmeterol No deaths; only 2 intubations (both in fluticasone alone group); overall no difference in serious adverse events Fewer severe asthma exacerbations in group treated with fluticasone + salmeterol. Combination ICS and LABA Combination Brand name Dose per inhalation Fluticasone + salmeterol Advair DPI Advair HFA AirDuo DPI 100/50, 250/50, 500/50 44/21, 115/21, 230/21 55/14, 113/14, 232/14 Budesonide + Symbicort HFA 80/4.5, 160/4.5 formoterol Mometasone + formoterol Dulera HFA 100/5, 200/5 Stempel DA, et al, NEJM 2016; 374:1822. Fluticasone furoate + Vilanterol Breo DPI 100/25, 200/25

8 Safety of LABAs in Combination with ICS: Implications Outline Stepping down therapy in patients on LABA and high dose ICS Single inhaler maintenance and rescue therapy Intermittent use of LABA / ICS combination in mild persistent asthma Measurement of exhaled nitric oxide Safety of long acting beta agonists Anticholinergic bronchodilators (LAMAs) New medication delivery devices Biologics in severe asthma Alternative Long Acting BD: Anti Cholinergic (Tiotropium) ICS + Tiotropium in Asthma (TALC) 210 subjects with asthma poorly controlled on beclomethasone 160 mcg/day Randomly assigned to: Beclomethasone 320 mcg/day Beclo 160 mcg/day + Salmeterol BID Beclo 160 mcg/day + Tiotropium qd Adding tiotropium to ICS was non inferior to adding salmeterol in all outcomes measured. Peters SP, et al (ACRN). NEJM 2010; 363: Peters SP, et al (ACRN). NEJM 2010; 363:

9 Two RCTs involving 912 subjects, all symptomatic despite high dose ICS and LABA Two RCTs involving 912 subjects, all symptomatic despite high dose ICS and LABA Compared to placebo, tiotropium improved lung function (trial 1 = 86 ml, trial 2 = 154 ml); Kerstjens HAM, et al. NEJM 2012; 367: Kerstjens HAM, et al. NEJM 2012; 367: Other Long Acting Muscarinic Antagonists (LAMAs) not yet approved for asthma Two RCTs involving 912 subjects, all symptomatic despite high dose ICS and LABA Compared to placebo, tiotropium improved lung function (trial 1 = 86 ml, trial 2 = 154 ml); and Increased the time to first severe exacerbation (282 vs 226 days), with 21% decrease in risk of severe exacerbation. Umeclidinium (Incruse DPI) Glycopyrollate (Lonhala neb solution) Revafenacin (Yulpelri neb solution)

10 Efficacy of Anticholinergic Bronchodilators (LAMAs) in Asthma: Implications Alternative to LABAs in patients intolerant of LABAs Relatively low cost add on therapy in severe asthma Potential future role of LABA / LAMA / ICS combination inhalers in asthma Outline Measurement of exhaled nitric oxide Safety of long acting beta agonists Anticholinergic bronchodilators (LAMAs) New medication delivery devices Biologics in severe asthma Types of Inhalers Outline Metered dose inhalers Dry powder inhalers Single dose Multi dose Soft mist inhalers Measurement of exhaled nitric oxide Safety of long acting beta agonists Anticholinergic bronchodilators (LAMAs) New medication delivery devices Biologics in severe asthma

11 Asthma Endotypes It is increasingly clear that asthma is a complex disease made up of number of disease variants with different underlying pathophysiologies. Limited knowledge of the mechanisms of these disease subgroups is possibly the greatest obstacle in understanding the causes of asthma and improving treatment. Lötvall J, et al. J Allergy Clin Immunol 2011; 127: Asthma Endotypes Aspirin sensitive asthma Allergic asthma (adults) Severe late onset hypereosinophilic asthma Allergic bronchopulmonary aspergillosis Eosinophilic granulomatosis and polyangiitis Asthma with irreversible airflow obstruction Arachidonic Acid Pathway Membrane Phospholipids Phospholipase A 2 Arachidonic Acid Pathway Membrane Phospholipids Phospholipase A 2 Cyclooxygenase Prostaglandins Thromboxanes Arachidonic Acid 5 lipoxygenase Leukotrienes C 4, D 4, E 4 Cyclooxygenase Prostaglandins Thromboxanes Arachidonic Acid 5 lipoxygenase Leukotrienes C 4, D 4, E 4 Zileuton Montelukast Zafirlukast Cysteinyl leukotriene receptor Cysteinyl leukotriene receptor

12 Arachidonic Acid Pathway Aspirin NSAIDs Cyclooxygenase Prostaglandins Thromboxanes Membrane Phospholipids Arachidonic Acid Phospholipase A 2 5 lipoxygenase Leukotrienes C 4, D 4, E 4 Aspirin Exacerbated Respiratory Disease Treatment: Aspirin desensitization followed by aspirinmaintenance therapy Cysteinyl leukotriene receptor Severe Asthma Biochemical Pathways in Severe Asthma NEJM 2017: 377: Israel E, et al. NEJM 2017: 377:

13 Targeted Monoclonal Antibodies High IgE level: Anti IgE (omalizumab, Xolair) High peripheral blood eosinophils: Anti IL 5 (mepolizumab, Nucala; and reslizumab, Cinqair ) Anti IL 5Rα (benralizumab, Fasenra) Anti IL 4Rα (dupilumab, Dupixent) Anti IL 5 for Moderate Asthma Am J Respir Crit Care Med 2007; 176: Mepolizumab in Eosinophilic Asthma Benralizumab: Change from Baseline in the Oral Glucocorticoid Dose and Asthma Exacerbations Ortega HG et al, NEJM 2014; 371:1198. Bel EH, et al, NEJM 2014; 371:1189. Nair P, et al., N Engl J Med 2017; 376:

14 Benefits of Biologics Negatives of Biologics Fewer exacerbations (Slightly) improved lung function Improved asthma quality of life Lowered steroid dose COST! Indeterminate duration of therapy Bronchial Thermoplasty Bronchial Thermoplasty Procedure: 3 bronchoscopies over 6 weeks Benefits: Improved quality of life; fewer exacerbations Risks: Bronchoscopy associated asthmatic exacerbations, complications

15 Trends in Asthma Deaths in U.S. Epidemiology of Asthmatic Attacks Trends in Asthma Statistics, Feb American Lung Association 3,400 deaths/year 439,000 hospitalizations/year 2.1 million ED visits/year Asthma Fact Sheet, 2012 American Lung Association (data for 2009) Summary Summary (cont.) Exhaled nitric oxide concentration can be used as a non invasive marker of eosinophilic airway inflammation. Long acting beta agonist bronchodilators (LABA s) are safe when used in combination with inhaled corticosteroids. Long acting muscarinic antagonist bronchodilators (LAMAs) are an alternative to LABAs and can be added to LABA/ICS combination. Effective inhaler technique remains crucial to successful asthma treatment and should be a major focus of patient education.

16 Summary (cont.) Novel biologic therapies are available for the treatment of severe, refractory asthma in patients with Type 2 asthmatic inflammation.