![Faculty: [Dr Dave Williams]
Relationships with commercial interests
Speakers bureau/honoraria: Boehringer Ingelheim (Canada) Ltd.
Faculty/presenter disclosure](data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7)
Recommandé
Contenu connexe
Tendances
Tendances (20)
En vedette
En vedette (20)
Similaire à Module 4 lama lab_as
Similaire à Module 4 lama lab_as (20)
Dernier
Dernier (20)
Module 4 lama lab_as
- 1. Continuum of Care in COPD: Making Sense of New Treatment Options
- 2. Faculty: [Dr Dave Williams] Relationships with commercial interests Speakers bureau/honoraria: Boehringer Ingelheim (Canada) Ltd. Faculty/presenter disclosure
- 3. This program has received financial support through Boehringer Ingelheim (Canada) Ltd. This program has received in-kind support from Boehringer Ingelheim (Canada) Ltd. in the form of logistical support and provision of the meal/refreshments Potential for conflict(s) of interest: Speaker has received an honorarium from Boehringer Ingelheim (Canada) Ltd. to present this program Boehringer Ingelheim (Canada) Ltd. developed and distributes the following products that may be discussed in this program: tiotropium (Spiriva® HandiHaler®, Spiriva® Respimat®), ipratropium/salbutamol (Combivent® Respimat®) Disclosure of commercial support
- 4. What Do I Do Next? I Started With Prescribing a LAMA for My Patient; Now Where Do I Go?
- 5. Recognize the difference between LABA and LAMA and combination therapies in more complex patients Identify the benefits/limitations of monotherapies and combination therapies based on the severity of COPD Outline pharmacotherapy treatment progression from monotherapy to triple therapy based on the severity of COPD Learning objectives LABA, long-acting beta 2 agonist.
- 6. Linda is a 71-year-old retired executive assistant who enjoys playing with her grandchildren and gardening, although lately she has had a lot of trouble doing both due to shortness of breath She quit smoking 10 years ago and has a 90 pack-year history Case study
- 7. She was diagnosed with COPD 8 years ago; she was placed on a tiotropium HandiHaler once daily and salbutamol as needed She recently presented to the emergency department with persistent dyspnea, cough, and purulent sputum She had another exacerbation several years ago Case study
- 8. FEV1 40% FEV1/FVC 0.59 MRC grade 4 Post-bronchodilator spirometry results for Linda FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; MRC, Medical Research Council.
- 9. What would you do next to help improve Linda’s symptoms?
- 10. Goals of management of COPD Relieve symptoms Improve exercise tolerance Improve health status Prevent disease progression Prevent and treat exacerbations Reduce mortality GOLD, Global Initiative for Chronic Lung Disease. Consistent with O’Donnell et al. Can Respir J 2008, CTS guidelines. GOLD guidelines, 2014. Reduce symptoms Reduce risk
- 11. Stepwise management approach for COPD AECOPD, acute exacerbation of COPD; PRN, as needed. O’Donnell et al. Can Respir J 2008;CTS guidelines. Prevent / Rx AECOPD Follow-up Early diagnosis (spirometry) + prevention End-of-life care Smoking cessation/exercise/self-management education PRN short-acting bronchodilator(s) Long-acting bronchodilator(s) Pulmonary rehabilitation Inhaled corticosteroids/LABA Surgery Oxygen Lung function impairment MRC dyspnea scale MILD VERY SEVERE 2 5
- 12. Dual LABA/LAMA and low-dose ICS in triple therapy may be used for infrequent AECOPDs *Refers to lower-dose ICS/LABA. ICS, inhaled corticosteroid; LAAC, long-acting anticholinergic; SABA, short-acting beta 2 agonist; SABD, short-acting bronchodilator. O’Donnell et al. Can Respir J 2008;CTS guidelines. Increasing disability and lung function impairment VERY SEVEREMILD MODERATE SABD prn Persistent dyspnea LAAC + SABA prn LABA + SABD prn or Persistent dyspnea Persistent dyspnea Persistent dyspnea LAAC or LABA + SABA prn LAAC + LABA + SABA prn LAAC + ICS/LABA* + SABA prn LAAC + ICS/LABA + SABA prn LAAC + ICS/LABA + SABA prn Theophylline ± Frequent AECOPD (≥ 1 per year) Infrequent AECOPD (average of < 1 per year) VERY SEVERE
- 13. Increasing complexity in new marketplace What to do? When to do it? With what patients? Benefits and risks? orFor 10+ years NOW LAMA LAMA ICS/LABAICS/LABA LAMA LABA LABA/LAMA ICS/LABA
- 14. LAMA inhalers for COPD in Canada LAMA DPI HandiHaler/ SMI Respimat Spiriva®§ (tiotropium) DPI Breezhaler Seebri® (glycopyrronium)* DPI Genuair Tudorza® (aclidinium)* DPI Ellipta Incruse® (umeclidinium)* CLASS INHALER NAME BRAND NAME/ GENERIC NAME Recently approved (since 2012). DPI, dry powder inhaler; SMI, soft mist inhaler. § Spiriva® Respimat is also approved for reduction of exacerbations.
- 15. The MCID in outcomes of therapy for patients with COPD has been proposed as a tool to assist clinicians in understanding the results of clinical trials ‘‘The smallest difference in score in the outcome of interest that informed patients or informed proxies perceive as important, either beneficial or harmful, and which would lead the patient or clinician to consider a change in management’’ Minimal Clinically Important Difference MCID, minimal clinically important difference. Cazzola M, et al. Eur Respir J 2008;31:416-69.
- 16. MCIDs for common outcomes in COPD TDI, Transition Dyspnea Index. 1. Cazzola M, et al. Eur Respir J 2008;31:416-69. 2. Donohue JF. COPD 2005;2:111-24. 3. Mahler DA and Witek TJ Jr. COPD 2005;2:99-103. 4. Schunemann H et al. J Clin Epidemiol 2003;56(12):1170-6. 5. Jones PW. COPD 2005;2:75-9. 6. Pepin V et al. Thorax 2011;66:115-20. 7. Puhan MA et al. Eur Respir J 2008;32:637-43. Lung function: trough FEV1 100–140 mL1,2 Exacerbations No validated MCID Dyspnea: TDI total score 1 unit3 Dyspnea: CRQ 0.5 units4 Health status: SGRQ total score 4 units5 Exercise capacity: endurance shuttle walking test 45–85 s (60–115 min)6 Exercise capacity: 6 min walk test ≥35 min7 ENDPOINT MCID (IMPROVEMENT)
- 17. Trials assessing tiotropium (LAMA) M = MCID; * = statistically significant. HRQL, health-related quality of life. 1. Casaburi et al. Eur Respir J 2002;19:217-24. 2. Donohue et al. Chest 2002;122:47-55. 3. Vincken et al. Eur Respir J 2002;19:209-16. 4. O’Donnell et al. Eur Respir J 2004;23:832-40. 5. Dusser et al. Eur Respir J 2006;27:547-55. 6. Tashkin et al. N Engl J Med 2008;359:1543-54. 7. Vogelmeier et al. N Engl J Med 2011;364:1093-103. 8. Cooper et al. Chest 2013;144:490-7. TRIAL YEAR N DURATIO N COMPARATOR BENEFIT SHOWN OVER COMPARATOR(S)? LUNG FUNCTION EXACERBATIONS HRQL DYSPNEA EXERCISE ENDURANCE Casaburi1 2002 9,211 1 y Placebo *M * *M *M Donohue2 2002 623 6 mos Salmeterol Placebo * *M * *M * *M Vincken3 2002 535 1 y lpratropium *M * * *M O’Donnell4 2004 187 42 d Placebo *M *M *M Dusser5 2006 1,100 1 y Placebo *M * UPLIFT6 2008 5,993 4 y Control * * *M POET-COPD7 2011 7,376 1 y Salmeterol * Cooper8 2013 519 2 y Control * *M The above trials assessed tiotropium delivered via HandiHaler, approved in Canada in 2002; the safety and efficacy of tiotropium delivered via Respimat device were recently shown to be similar (Wise et al N Engl J Med 2013). • Overall, tiotropium shows clinically meaningful improvement in all measures of lung function, HRQL, dyspnea, and exercise endurance • Spiriva Respimat is the only LAMA that has Health Canada approval for reduction in exacerbations
- 18. Tiotropium administered through an SMI is as effective as through a HH SMIs are simple to coordinate, and the delivered dose is independent of inspiratory effort Time post-dosing (minutes and hours) FEV1(L) 10h 12h8h6h4h3h2h1h 30min 15min -10min 1.00 1.04 1.08 1.12 1.16 1.20 1.32 1.28 1.24 Tiotropium 5 µg SMI (n = 187) Tiotropium 10 µg SMI (n = 179) Tiotropium 18 µg HH (n = 186) Placebo (n = 181) ** * HH, HandiHaler.
- 19. Trials assessing recently approved LAMAs 1. D’Urzo et al. Respir Res 2011;12:156. 2. Kerwin et al. Eur Respir J 2012;40:1106-14. 3. Beeh et al. Int J Chron Obstruct Pulmon Dis 2012;7:503-13. 4. Chapman et al. BMC Pulm Med 2014;14:4. 5. Kerwin et al. COPD 2012;9:90-101. 6. Jones et al. Eur Respir J 2012;40:830-6. 7. Donohue et al. Respir Med 2013;107:1538-46. 8. Trivedi et al. Eur Respir J 2014;43:72–81. 9. Church et al. BMC Pulm Med 2014;14:2. TRIAL YEAR N DURATION COMPARATOR BENEFIT SHOWN OVER COMPARATOR? EXACERBATIONS HRQL DYSPNEA GLYCOPYRRONIUM (Seebri; approved in Canada in 2012) GLOW1 2011 822 26 w Placebo *M * *M GLOW2 2012 1,066 1 y Placebo, OL-tiotropium *M - * - GLOW33 2012 108 3 w Placebo *M * GLOW54 2014 657 12 w Tiotropium - - - - ACLIDINIUM (Tudorza; approved in Canada in 2013) ACCORD 15 2012 561 12 w Placebo *M *M *M ATTAIN6 2012 828 24 w Placebo *M *M *M UMECLIDINIUM (lncruse; approved in Canada in 2014) Donohue7 2013 1,532 24 w Placebo *M * *M Trivedi8 2014 206 12 w Placebo *M * *M Church9 2014 163 8 d Placebo OL-tiotropium *M - LUNG FUNCTION EXERCISE ENDURANCE • Overall, the new LAMAs show clinically meaningful improvements in some outcomes compared to placebo, but not compared to tiotropium • More data on exercise endurance is needed
- 20. LABA inhalers for COPD in Canada LABA DPI Diskus Serevent® (salmeterol) DPI Aerolizer Foradil® (formoterol) DPI Breezhaler Onbrez® (indacaterol) CLASS INHALER NAME BRAND NAME/GENERIC NAME
- 21. Trials assessing LABAs 1. Calverley et al. NEJM 2007; 356(8):775-789 2. Donohue et al. Chest 2002:122:47-55. 3. Vogelmeier et al. NEJM 2011; 364:1093-103. 4. Dahl R et al. Am J Respir Crit Care Med. 2001 Sep 1;164(5):778-84. 5. Rossi A et al. Chest 2002 Apr;121(4):1058-69. 6. & 7. Reported in CDER summary review document for indacaterol 2011. TRIAL YEAR N DURATION COMPARATOR BENEFIT SHOWN OVER COMPARATOR? EXACERBATIONS HRQL DYSPNEA SALMETEROL (Serevent) Calverley 1 2007 6112 3 yrs Placebo +Fluticasone * - * - - - Donohue2 2002 623 6 mos Placebo Tiotropium * - - - - - POET-COPD3 2011 7,376 1 y Tiotropium - FORMOTEROL (Foradil) Dahl4 2001 780 12 w Placebo Ipratropium *M * *M - Rossi5 2002 854 12 mths Placebo OL-theophylline *M * *M - INDACATEROL (Onbrez) B23546 2011 323 12 w Placebo *M * *M B23557 2011 318 12 w Placebo *M * LUNG FUNCTION EXERCISE ENDURANCE • Overall, LABAs shows clinically meaningful improvement measures of lung function, HRQL and dyspnea over placebo • The effects of LABAs on improvement in exercise endurance has been inconsistent
- 22. Combination LABA/LAMA inhalers for COPD in Canada * Approved Dec 2013 ** Approved May 2015 ***Approved April 2015 Fixed-dose combination LABA/LAMA DPI Ellipta Anoro® (vilanterol/umeclidinium)* DPI Breezhaler Ultibro® (indacaterol/glycopyrronium)* SMI Respimat Inspiolto® (olodaterol/tiotropium)** DPI Genuair Duaklir® (formoterol/aclidinium)*** CLASS INHALER NAME BRAND NAME/ GENERIC NAME
- 23. Trials assessing fixed dose LABA/LAMA: vilanterol /umeclidinium HRQL, health-related quality of life; VI, vilanterol. 1. Donohue et al. Respir Med 2013;107:1538-46. 2. Maleki-Yazdi et al. Respir Med 2014;108:1752-60. 3. Decramer et al. Lancet Respir Med 2014;2:472-86. TRIAL YEAR N DURATION COMPARATOR BENEFIT SHOWN OVER COMPARATOR? HRQL DYSPNEA Vilanterol/umeclidinium (Anoro Ellipta; approved in Canada in 2013) Donohue1 2013 1,532 24 w Vilanterol Umeclidinium Placebo * * *M *M - *M - - *M Maleki-Yazdi2 2014 905 24 w Tiotropium *M * Decramer3 2014 846 24 w Vilanterol Umeclidinium Tiotropium * - * LUNG FUNCTION EXERCISE ENDURANCE EXACERBATIONS The approved dosage of Anoro Ellipta in Canada is 25/62.5 µg. • There are clinically meaningful improvements for VI/UMEC in lung function, HRQL, and dyspnea over placebo • Inconclusive evidence vs. LAMAs (not all studies used Canadian approved dose) • There is no data on VI/UMEC combination therapy for exacerbations or exercise endurance
- 24. Trials assessing fixed dose LABA/LAMA: indacaterol/glycopyrronium 1. SHINE: Bateman et al. ERJ Express 2013. 2. ILLUMINATE: Vogelmeier C et al. Lancet Respir Med. 2013;1(1):51-60 . 3. SPARK: Wedzicha et al. Lancet Respir Med. 2013;1(3):199-209. 4. BRIGHT: Beeh KM et al. Respir Med 2014;108:584-92. 5. ENLIGHTEN: Dahl R et al. Respir Med 2013;107:1558-67. TRIAL YEAR N DURATION COMPARATOR BENEFIT SHOWN OVER COMPARATOR? EXACERBATIONS HRQL DYSPNEA INDACATEROL/GLYCOPYRRONIUM (Ulitbro Breezhaler approved in Canada in Dec 2013) SHINE1 2013 380 26 w Indacaterol Glycopyrronium OL-Tiotropium Placebo * * * *M - - * *M - - * *M ILLUMINATE2 2012 523 26 w Salmeterol- fluticasone *M * SPARK3 2013 2,224 64 w Glycopyrronium OL-Tiotropium * *M - - *M *M BRIGHT4 2014 85 3 w Tiotropium Placebo *M *M - *M ENLIGHTEN5 2013 339 52 w Placebo *M LUNG FUNCTION EXERCISE ENDURANCE • Indacaterol/glycopyrronium shows MCID for lung function over placebo and salmeterol/fluticasone • MCID for HRQL, dyspnea, and exercise endurance over placebo • Some studies show MCID for lung function vs. OL- tiotropium and tiotropium, one study does not show MCID vs. OL-tiotropium
- 25. Trials assessing fixed dose LABA/LAMA: olodaterol/tiotropium 1. Beeh KM et al. Pulm Pharmacol Ther 2015; May 6 pii: S1094-5539(15)00044-9. 2. Buhl R et al. Eur Respir J 2015: 45(4):969-79. . TRIAL YEAR N DURATION COMPARATOR BENEFIT SHOWN OVER COMPARATOR? EXACERBATIONS HRQL DYSPNEA OLODATEROL/TIOTROPIUM (Inspiolto Respimat approved in Canada in June 2015) Beeh1 2015 259 6 w Olodaterol Tiotropium Placebo *M *M *M Buhl2 2015 5162 52 w Olodaterol Tiotropium * * - - *M *M *M *M LUNG FUNCTION EXERCISE ENDURANCE • Olodaterol/tiotropium shows MCID for lung function (FEV1 AUC0-24) over placebo and monotherapies • Statistical significant difference in trough FEV1 over monotherapies • MCID for HRQL and dyspnea over monotherapies
- 26. Olodaterol/tiotropium improved lung function compared to monotherapies Buhl R et al. Eur Respir J 2015: 45(4):969-79.
- 27. Trials assessing fixed dose LABA/LAMA: formoterol/aclidinium 1. AUGMENT: D’Urzo AD et al. Respir Res 2014; 15:123. 2. ACLIFORM-COPD: Singh D et al. BMC Pulmon Med 2014; 14:178. TRIAL YEAR N DURATION COMPARATOR BENEFIT SHOWN OVER COMPARATOR? EXACERBATIONS HRQL DYSPNEA OLODATEROL/TIOTROPIUM (Inspiolto Respimat approved in Canada in June 2015) AUGMENT1 2014 1692 24 w Aclidinium Formoterol Placebo - * *M - - *M - - *M ACLIFORM- COPD2 2014 2443 24 w Aclidinium Formoterol Placebo - * *M - - - - - *M - - *M LUNG FUNCTION EXERCISE ENDURANCE• Formoterol/aclidinium shows MCID for lung function, HRQL and dyspnea over placebo • Statistical significant difference in trough FEV1 over formoterol • No difference in HRQL and dyspnea over monotherapies
- 28. Formoterol/aclidinium shows MCID in lung function vs. placebo AUGMENT: D’Urzo AD et al. Respir Res 2014; 15:123.
- 29. Linda experiences two more exacerbations over the next year. Would you change her treatment?
- 30. Patients who have a lung attack are twice as likely to die in the 12 months following a hospital stay than patients who have had a heart attack 8% of patients die in hospital following an exacerbation 25% of patients die within one year of being hospitalized Lung attacks (exacerbations) are to COPD what heart attacks are to coronary artery disease http://www.torontosun.com/2012/02/21/copd-patients-not-reporting-lung-attacks-report Groenewegen KH et al. Chest 2003;124:459-67. Thom T et al. Circulation 2006;113:e85-e151. Nie JX et al. Can Respir J 2007;14(8):485-9.
- 31. Exacerbations correlate with poor outcomes GOLD Guidelines. Jenkin et al. Respir Res 2009:10:59. Decramer et al. Lancet 2009;374:1171-8. Hurst et al. N Engl J Med 2010;363:1128-38. *Toward a Revolution in COPD Health (TORCH) study Understanding Potential Long-Term Impacts on Function with Tiotropium (UPLIFT) study ≠Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study GOLD spirometric level Exacerbations (per year)*≠ Hospitalizations (per year)*≠ 3-year mortality* GOLD 1: Mild ? ? ? GOLD 2: Moderate 0.7–0.9 0.11–0.2 11%* GOLD 3: Severe 1.1–1.3 0.25–0.3 15%* GOLD 4: Very severe 1.2–2.0 0.4–0.54 24%* Risk in COPD: Placebo-limb data from TORCH,* Uplift, and Eclipse≠
- 32. Frequent exacerbations are associated with an accelerated loss of FEV1 Adapted from Makris D et al. Respir Med 2007;101:1305-12. AnnualdeclineinFEV1%predicted Smoker (n = 44) Ex-smoker (n = 58) Infrequent Frequent(2.85 per year) P = 0.017 -3.15 -4.1 -0.85 -2.8 -5 -4 -3 -2 1 0
- 33. Nonpharmacological therapies for COPD patient at risk for AECOPD 2014 CHEST-CTS Guideline: Prevention of Acute Exacerbation of Chronic Obstructive Pulmonary Disease. AECOPD = e.g. acute event that requires antibiotic and/or systemic corticosteroids (moderate: at home, doctor’s office or ER; severe: in hospital) SUGGESTED • Pneumococcal vaccine • Smoking cessation • Education and action plan and case management RECOMMENDED • Annual influenza vaccine • Pulmonary rehabilitation (AECOPD ≤ 4 weeks) • Education and case management with monthly follow-up NOT SUGGESTED • Pulmonary rehabilitation (AECOPD > 4 weeks) • Education or case management alone • Education with action plan but without case management • Telemonitoring
- 34. Triple therapy is recommended for severe COPD with frequent AECOPDs *Refers to lower-dose ICS/LABA. O’Donnell et al. Can Respir J 2008, CTS guidelines. Increasing disability and lung function impairment VERY SEVEREMILD MODERATE SABD prn Persistent dyspnea LAAC + SABA prn LABA + SABD prn or Persistent dyspnea Persistent dyspnea Persistent dyspnea LAAC or LABA + SABA prn LAAC + LABA + SABA prn LAAC + ICS/LABA* + SABA prn LAAC + ICS/LABA + SABA prn LAAC + ICS/LABA + SABA prn Theophylline ± Frequent AECOPD (≥ 1 per year) Infrequent AECOPD (average of < 1 per year) VERY SEVERE
- 35. Pharmacological oral therapies for COPD patient at risk for AECOPDs PDE4, phosphodiesterase 4. 2014 CHEST-CTS Guideline: Prevention of Acute Exacerbation of Chronic Obstructive Pulmonary Disease. AECOPD = e.g. acute event that requires antibiotic and/or systemic corticosteroids (moderate: at home, doctor’s office or ER; severe: in hospital) NOT RECOMMENDED • Systemic corticosteroids in an attempt to decrease AECOPDs > 30 days after initial event • Statins SUGGESTED • Long-term macrolides • PDE4 inhibitors • N-acetylcysteine • Carbocysteine
- 36. Combination ICS/LABA inhalers for COPD in Canada ICS/LABA DPI Diskus Advair® (Fluticasone/salmeterol) DPI Turbuhaler Symbicort® (Budesonide/formoterol) DPI Ellipta Breo® (Fluticasone/vilanterol) CLASS INHALER NAME BRAND NAME/ GENERIC NAME
- 37. ICS use increases the risk of pneumonia1-3 ICSs should be avoided in most patients with infrequent exacerbations (< 1/year)4 Patients with frequent exacerbations (≥ 1/year) may benefit from ICSs,4 but: ▪ LAMA+LABA therapy is recommended prior to considering addition of ICS4 ▪ Patients with ACOS may benefit from ICS/LABA or LAMA/LABA/ICS therapy4 Inhaled corticosteroids in COPD management ACOS, asthma-COPD overlap syndrome. 1. Suissa et al. Thorax 2013;68:1029-36. 2. Yang et al. Cochrane Database Syst Rev 2012;7:CD002991. 3. Nannini et al. Cochrane Database Syst Rev 2012;9:CD006829. 4. O’Donnell et al. Can Respir J. 2008:15(suppl A):1A-8A.
- 38. ASTHMA COPD ACOS Age of onset Usually < 40 years Usually > 40 years Usually > 40 years (but may have had symptoms earlier) Smoking history Not causal Usually > 10 pack-years Sometimes Sputum production Infrequent Often Often Allergies Often Infrequent Often Disease course Stable (with exacerbations) Progressive worsening (with exacerbations) Progressive worsening (with exacerbations) Spirometry Often normalizes May improve but never normalizes May improve, historical variability Clinical symptoms Intermittent and variable Persistent Variability may be prominent Asthma-COPD overlap syndrome accounts for 15 to 20% of obstructive airway diseases O’Donnell et al. Can Respir J. 2008:15(suppl A):1A-8A. Global Strategy for Asthma Management and Prevention, 2014.
- 39. TRIAL YEAR N DURATION COMPARATOR BENEFIT SHOWN OVER COMPARATOR? HRQL FLUTICASONE/SALMETEROL (Advair) Kardos1 2007 994 44 w Salmeterol * Pneumonia TORCH2 2007 6,112 3 y Components Placebo * * * * * * Pneumonia INSPIRE3 2008 1,323 2 y Tiotropium - - * Mortality Pneumonia BUDESONIDE/FORMOTEROL (Symbicort) CLIMB4 2009 660 12 w +Tiotropium vs. Tiotropium alone *M * * Sharafkhaneh5 2012 1,219 1 y Formoterol * * Pneumonia FLUTICASONE/VILANTEROL (Breo; approved in Canada in 2013) Kerwin6 2013 1,224 24 w Components Placebo * * Martinez7 2013 1,030 24 w Fluticasone Vilanterol Placebo *M - *M Dransfield8 2013 3,255 1 y Vilanterol * Pneumonia Trials assessing approved fixed-dose ICS/LABA combination therapies 1. Kardos et al. Am J Resp Crit Care Med 2007;175:144-9. 2. Calverley et al. N Engl J Med 2007;356:775-89. 3. Wedzicha et al. Am J Resp Crit Care Med 2007;177:19- 26. 4. Welte et al. Am J Resp Crit Care Med 2009;180:741-50. 5. Sharafkhaneh et al. Respir Med 2012;106:257-68. 6. Kerwin et al. Respir Med 2013;107:560-9. 7. Martinez et al. Respir Med 2013;107:550-9. 8. Dransfield et al. Lancet Respir Med 2013;1:210-23. LUNG FUNCTION EXERCISE ENDURANCE OTHER FINDINGS EXACERBATIO N DYSPNEA • ICS/LABA improved exacerbation rates compared to components and placebo, but not vs. tiotropium • Mixed results for MCID in lung function vs. comparators • Increased risk of pneumonia
- 40. Stepwise withdrawal of ICS was not associated with an increased risk of exacerbations Inhaled glucocorticoid (IGC) = inhaled corticosteroid (ICS). Magnussen H et al. N Engl J Med 2014;371:1285-94. IGC withdrawal 0.0 0.1 0.9 Estimatedprobability 0.2 0.3 0.5 0.4 0.6 0.7 0.8 1.0 0 6 12 18 24 30 36 42 48 54 Weeks to event Moderate or severe COPD exacerbation Hazard ratio 1.06 (95% CI 0.94–1.19) P = 0.35 by Wald’s chi-square test IGC continuation Tiotropium+ fluticasone/salmeterol Tiotropium + salmeterol
- 41. Lung function was not severely impacted in patients with stepwise withdrawal of ICS SE, standard error. Adapted from Magnussen H et al. N Engl J Med 2014;371:1285-94. Adjustedmean(SE)change frombaselineinFEV1(mL) **P < 0.01; ***P < 0.0001 vs. ICS; restricted maximum likelihood repeated measures model; baseline values 970 mL for ICS, 981 mL for ICS withdrawal Week Tiotropium + salmeterol with stepwise withdrawal of fluticasone 100 µg BID 0 µg (placebo)250 µg BID ICS withdrawal Tiotropium + fluticasone/salmeterol 38 mL 43 mL *** **
- 42. Budesonide/formoterol added to tiotropium decreased exacerbations vs. tiotropium alone BUD, budesonide; FORM, formoterol; PBO, placebo; TIO, tiotropium. Welte et al. Am J Respir Crit Care Med 2009;180:741-50. 0 0.1 0 Exacerbations/patient Days since randomization 15 30 45 60 75 90 0.2 0.3 0.4 PBO + TIO BUD/FORM + TIO 0.38 (95% CI, 0.25–0.57; P < 0.001)
- 43. Dual therapy and triple therapy may be effective in moderate to severe COPD M, reaching MCID; *, statistically significant; ↑ improvement; ↓ decrease. Adapted from Rodrigo GJ et al. Pulm Pharm Ther 2012;25:40-47. FEV1 ↑*M ↑* ↑*M Dyspnea ↓*M ↓* ↓ HRQL ↑* ↑* ↑*M COPD exacerbations No difference (“Long duration” studies suggest a reduction compared with “short duration” studies) ↓ SAE ↑* ↑ LABA + tiotropium vs. tiotropium (“Dual” therapy) ICS/LABA vs. tiotropium (“Combined” therapy) ICS/LABA + tiotropium vs. tiotropium (“Triple” therapy) • LABA/tiotropium vs. tiotropium shows MCID in lung function and dyspnea, but not in health status or exacerbations • ICS/LABA vs. tiotropium does not result in MCID for any health outcome • ICS/LABA + tiotropium vs. tiotropium shows MCID for lung function and health status, but not in dyspnea or exacerbations
- 44. Possible progression from LAMA to dual, combined, or triple therapy LAMA LABA/ LAMA LABA/ ICS LAMA + ICS/LABA • Better lung function • Incremental improvements in HRQL and dyspnea • No difference in exercise endurance or exacerbations • Statistically significant but not MCID compared to LAMA for lung function, dyspnea, HRQL, or exacerbations • Increased risk of pneumonia • Better lung function and HRQL • No difference in dyspnea • Improvement in exacerbations • Increased risk of pneumonia
- 45. Possible next step from triple therapy Magnussen H et al. N Engl J Med 2014;371:1285-94. Wurst KE et al. PLoS One 2014;9(9):e105296. LAMA + ICS/LABA LAMA/LABA (stepwise withdrawal of ICS) • No significant change in lung function • No significant change in exacerbations Other expert recommendations? What does the patient look like: •Stable COPD •No history of exacerbations •No suspected ACOS •….
- 46. Smoking cessation and a pulmonary rehabilitation program are integral components of COPD management For moderate COPD with infrequent exacerbations, start with a LAMA or LABA and transition to dual or triple therapy if symptoms persist Patients with severe COPD will achieve additional benefit from dual LABA/LAMA therapy over monotherapy (dyspnea, quality of life, and exacerbations) Summary and take-home messages
- 47. COPD exacerbations are a major cause of morbidity and mortality Patients with frequent exacerbations should be treated with triple therapy (LAMA/LABA/ICS) ICSs can be safely withdrawn in many moderate or severe COPD patients, even with a history of prior exacerbations Summary and take-home messages (cont)
- 48. Care must be taken to exclude ACOS and to closely monitor symptoms and spirometry if ICS therapy is tapered and withdrawn ICS therapy, particularly with fluticasone, is associated with increased pneumonia risk ICS dose re-evaluation should be part of COPD reassessment Summary and take-home messages (cont)
Notes de l'éditeur
- FEV1, forced expiratory value in 1 second; FVC, forced vital capacity.
- The minimal clinical important difference for the measures are as follows: SGRQ, ± 0.5 points CRQ, ± 4 points Exercise endurance (6-minute walking) ≥ 35 metres
- AECOPD, acute exacerbations of COPD. Key message: Vaccinations should be administered at earliest diagnosis of COPD to prevent exacerbations and benefit general health.
- ICS/LABA, inhaled corticosteroid/LABA (e.g. fluticasone/salmeterol; budesonide/formoterol); LAAC, long-acting anticholinergic (e.g. tiotropium); LABA, long-acting beta 2 agonist (e.g. salmeterol; formoterol); SABA, short-acting beta agonist (e.g. salbutamol; terbutaline); SABD, short-acting bronchodilator (e.g. ipratropium or SABA).
- DPI, dry powder inhaler; SMI, soft mist inhaler. All LAMAs are approved for maintenance bronchodilator treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema. Spiriva Respimat is also approved for reduction of exacerbations.
- CRQ, Chronic Respiratory Questionnaire; FEV1, forced expiratory volume in 1 second; SGRQ, St. George’s Respiratory Questionnaire; TDI, Transition Dyspnea Index.
- Take-home message: Overall, tiotropium shows clinically meaningful improvement in all measures of lung function, HRQL, dyspnea and exercise endurance. It also shows statistically significant improvement in exacerbations (there is no MCID for exacerbations currently). Spiriva Respimat is the only LAMA that has Health Canada approval for reduction in exacerbations. Placebo groups were allowed to continue their usual respiratory medication, including short-acting bronchodilators as needed, oral and inhaled steroids and theophylline, but were not allowed other long-acting anticholinergics or long-acting beta 2 agonists. Control groups were allowed to continue their usual respiratory medication, including short-acting bronchodilators as needed, oral and inhaled steroids and theophylline, and were also allowed to continue with long-acting beta 2 agonists. No other long-acting anticholinergic was allowed. Treatment groups were allowed to continue their usual respiratory medication, including short-acting bronchodilators as needed, oral and inhaled steroids and theophylline. Casaburi et al. Eur Respir J 2002;19:217-24 With chronic therapy, predose FEV1 (i.e. trough) was elevated 110 ± 10 to 130 ± 10 mL (11±1–13±1%) over baseline (mean ± SEM); this was superior to placebo by 120 ± 10 to 150 ± 20 mL (P&lt; 0.01) on the various assessment days. The proportion of patients who achieved a score of ≥ 1.0 (corresponding to a clinically important difference) in TDI focal score was significantly greater in the tiotropium group at all five assessment points (42–47%) than in the placebo group (29–34%) (P &lt; 0.01). The proportion of patients experiencing at least one COPD exacerbation was lower in the tiotropium group (36%) than in the placebo group (42%) (14% reduction, P &lt; 0.05). In addition to a statistically significant improvement in mean response, a significantly greater percentage of patients in the tiotropium group (49%) showed at least a four-unit improvement in total score, recognized as a clinically meaningful response, compared to those in the placebo group (30%). Donohue et al. Chest 2002;122:47-55 At 24 weeks, trough FEV1 had improved significantly above placebo by 137 mL in the tiotropium group and by 85 mL in the salmeterol group. The difference between tiotropium and salmeterol was significant (52 mL, P &lt; 0.01). Dyspnea (TDI): The proportion of patients within each group achieving a 1 U change was 42%, 35%, and 26% for the tiotropium, salmeterol, and placebo groups, respectively. The differences were significant for tiotropium vs. placebo (P 0.01) but not for salmeterol vs. placebo or for tiotropium vs. salmeterol. The proportion of patients within each group achieving a clinically meaningful change (at least 4 U) in the SGRQ total score was 51%, 40%, and 42% for the tiotropium, salmeterol, and placebo groups, respectively. Vincken et al. Eur Respir J 2002;19:209-16 At the end of 1 year, trough FEV1 was 120 mL above the day 1 baseline for patients receiving tiotropium and had declined by 30 mL for those receiving ipratropium (difference of 150 mL between groups, P&lt;0.001 at all time points). The proportion of patients who achieved a clinically meaningful difference in TDI focal score (improvement of 1 unit) at 1 year was significantly greater in the tiotropium group (31%) than in the ipratropium group (18%, P = 0.004). More patients in the tiotropium group than in the ipratropium group achieved the clinically meaningful improvement of 4 units in the SGRQ total score after 9 and 12 months (52% vs. 35% respectively, at 1 year, P = 0.001). O’Donnell et al. Eur Respir J 2004;23:832-40 Finally, there were parallel improvements in TDI, by an average of 1.7 units, as compared to placebo, indicating clinically relevant reductions in chronic activity-related dyspnea and functional capacity. Dusser et al. Eur Respir J 2006;27:547-55 At the end of the treatment period, tiotropium improved trough FEV1 by 0.12 ± 0.02 L (P &lt; 0.0001). The proportion of patients experiencing one or more exacerbation during the 1 year treatment period was significantly lower in the tiotropium group than in the placebo group (17% reduction; P &lt; 0.01). Patients treated with tiotropium had significantly fewer COPD exacerbations (35% reduction; P &lt; 0.001) and exacerbation days (37% reduction; P &lt; 0.001) than those treated with placebo. Tashkin et al. N Engl J Med 2008;359:1543-54 Mean absolute improvements in FEV1 in the tiotropium group were maintained throughout the trial (ranging from 87 to 103 mL before bronchodilation and from 47 to 65 mL after bronchodilation), as compared with the placebo group (P &lt; 0.001) (statistically significant but not MID). A higher proportion of patients in the tiotropium group than in the placebo group had an improvement of 4 units or more in the SGRQ total scores from baseline at 1 year (49% vs. 41%), 2 years (48% vs. 39%), 3 years (46% vs. 37%), and 4 years (45% vs. 36%) (P &lt; 0.001 for all comparisons). Vogelmeier et al. N Engl J Med 2011;364:1093-103 Tiotropium, as compared with salmeterol, increased the time to the first exacerbation (187 days vs. 145 days), with a 17% reduction in risk (hazard ratio, 0.83; 95% confidence interval [CI], 0.77 to 0.90; P &lt; 0.001). Tiotropium also increased the time to the first severe exacerbation (hazard ratio, 0.72; 95% CI, 0.61 to 0.85; P &lt; 0.001), reduced the annual number of moderate or severe exacerbations (0.64 vs. 0.72; rate ratio, 0.89; 95% CI, 0.83 to 0.96; P = 0.002), and reduced the annual number of severe exacerbations (0.09 vs. 0.13; rate ratio, 0.73; 95% CI, 0.66 to 0.82; P &lt; 0.001). Cooper et al. Chest 2013;144:490-7 The mean morning predose difference in FEV1 ranged from 75 ± 27 to 116 ± 22 mL, with the difference, favouring tiotropium, being 75 ± 27 mL at 96 weeks (P &lt; 0.01 for all differences). (statistically significant but not MID). SGRQ total score at 96 weeks improved with tiotropium vs. placebo by 4.03 units (P = 0.007).
- SMI, soft mist inhaler; HH, HandiHaler. Mean FEV1 (L) response* following treatment with tiotropium 5 or 10 µg Respimat SMI, tiotropium 18 µg HandiHaler or placebo at pharmacodynamic steady state (day 29). *Adjusted for centre, patient (within centre), period, period baseline and treatment. Tiotropium treatments were statistically significantly different from placebo (P &lt; 0.0001) at all post-dose time points. In a prespecified, pooled analysis of two 30-week, double-blind, double-dummy, crossover studies, 207 patients with COPD were randomized to receive once-daily tiotropium 5 µg or 10 µg (aqueous solution delivered via Respimat SMI), tiotropium 18 µg (inhalation powder via HandiHaler), or placebo. The primary endpoint was trough FEV1 response. Forced vital capacity, peak expiratory flow rate, rescue medication use, safety, and pharmacokinetics (in a subgroup of patients) were also assessed.
- HRQL, health-related quality of life; M, minimal clinically important difference; OL, open-label; *, statistically significant; -, not statistically significant. Take-home message: Overall, the new LAMAs show clinically meaningful improvements in some outcomes compared to placebo, but not compared to tiotropium. Clinically meaningful improvements in exercise endurance is lacking. Placebo groups were allowed to continue their usual respiratory medication, including short-acting bronchodilators as needed, oral and inhaled steroids, and theophylline, but were not allowed other long-acting anticholinergics or long-acting beta agonists. Treatment groups were also allowed to continue their usual respiratory medication, including short-acting bronchodilators as needed, oral and inhaled steroids, and theophylline. D’Urzo et al Respir Res 2011;12:156 Trough FEV1 was also significantly higher in the NVA237 group at the end of day 1 (1.414 ± 0.0075 L) and at week 26 (1.387 ± 0.0112 L), compared with placebo (1.309 ± 0.0099 L and 1.275 ± 0.0150 L, respectively; both P &lt; 0.001). The treatment difference was 105 ± 10.9 mL at the end of day 1 and 113 ± 16.5 mL at week 26 (both P &lt; 0.001). Patients receiving NVA237 had a significantly (P &lt; 0.001) greater TDI focal score at week 26 (1.84) compared with placebo (0.80), with a treatment difference of 1.04, which exceeded the 1-point treatment difference considered as clinically important. Kerwin et al Eur Respir J 2012;40:1106-14 Trough FEV1 at the end of day 1 and at weeks 26 and 52 in the NVA237 group was significantly higher vs. placebo and comparable to tiotropium. At the end of day 1 and at weeks 26 and 52, compared with placebo, the treatment difference in favour of NVA237 was 91, 134, and 108 mL, respectively (all P &lt; 0.001), while the difference in favour of tiotropium was 83, 84, and 89 mL, respectively (all P &lt; 0.001). Beeh et al Int J Chron Obstruct Pulmon Dis 2012;7:503-13 Dynamic IC at exercise isotime and trough FEV1 showed significant and clinically relevant improvements from day 1 of treatment that were maintained throughout the study. This was accompanied by inverse decreases in residual volume and functional residual capacity. NVA237 was superior to placebo (P&lt; 0.05) in decreasing leg discomfort (Borg CR10 scale) on day 21 and exertional dyspnea on days 1 and 21 (transition dyspnea index and Borg CR10 scale at isotime). Chapman et al BMC Pulm Med 2014;14:4 Least squares mean trough FEV1 for both glycopyrronium and tiotropium was 1.405 L at week 12, meeting the criterion for noninferiority (mean treatment difference: 0 mL, 95% CI: –32, 31 mL). Glycopyrronium demonstrated rapid bronchodilation following the first dose on day 1, with significantly higher FEV1 at all time points from 0–4 hours post-dose vs. tiotropium (all P &lt; 0.001). FEV1 area under the curve from 0–4 h (AUC0–4 h) post-dose with glycopyrronium was significantly superior to tiotropium on day 1 (P &lt; 0.001) and was comparable to tiotropium at week 12. Glycopyrronium demonstrated comparable improvements to tiotropium in TDI focal score, SGRQ total score, rescue medication use, and the rate of COPD exacerbations (all P = not significant). Patients on glycopyrronium also had a significantly lower total COPD symptom score vs. patients on tiotropium after 12 weeks (P = 0.035). Kerwin et al COPD 2012;9:90-101 At week 12, aclidinium 200 μg and 400 μg showed significant improvements from baseline in mean (95% CI) trough FEV₁ compared with placebo by 86 (45, 127) mL and 124 (83,164) mL. At study end, improvements in SGRQ total score over placebo were –2.7 (aclidinium 200 μg, P = 0.013) and –2.5 (aclidinium 400 μg, P = 0.019). At all time points, a higher percentage of patients in each aclidinium group (ranging from 41% [week 4, 400 μg] to 49% [week 12, 200 μg]) achieved a clinically meaningful improvement in SGRQ total score (≥4-point decrease from baseline) compared with placebo (ranging from 27% to 36%; P &lt; 0.05 for all vs. placebo based on odds ratios, except at week 12 for the aclidinium 400 μg group, P = 0.139). Similarly, both aclidinium doses significantly improved TDI focal scores compared with placebo at each study visit (P &lt; 0.05 for all, except at week 8 for aclidinium 200 μg, P = 0.060), with maximum differences from placebo for aclidinium 200 μg and 400 μg observed at week 4 (1.4) and week 12 (1.0), respectively (P &lt; 0.005 for both). Aclidinium 200 μg resulted in a 0.9 difference in TDI focal score from placebo at week 12 (P = 0.005). A higher percentage of patients in each aclidinium group (ranging from 48% [week 12, 400 μg] to 55% [week 4, 200 μg]) achieved a clinically meaningful improvement in TDI (≥ 1 unit) compared with placebo (ranging from 31% to 34%) at all time points (P &lt; 0.05 for all vs. placebo based on odds ratios). Jones et al Eur Respir J 2012;40:830-6 At week 24, significant improvements from baseline were observed with aclidinium 200 μg and 400 μg vs. placebo for trough FEV1 (99 and 128 mL; both P &lt; 0.0001). By week 24, the improvement over placebo in baseline-adjusted means SGRQ total score was -3.8 ± 1.1 units for aclidinium 200 μg (P&lt; 0.001) and -4.6 ± 1.1 units for aclidinium 400 μg (P &lt; 0.0001). More patients had a clinically significant improvement in SGRQ total score (≥ 4 units) at week 24 with aclidinium 200 μg and 400 μg compared with placebo (56.0% and 57.3% vs. 41.0%; odds ratio 1.83 and 1.87; P &lt; 0.001 for both). The improvement over placebo in baseline-adjusted means TDI focal score at week 24 was 0.6 ± 0.3 units for aclidinium 200 μg (P &lt; 0.05) and 1.0 ± 0.3 unit for aclidinium 400 μg (P &lt; 0.001). More patients treated with aclidinium 200 μg and 400 μg had a clinically significant improvement in TDI focal score (≥ 1 unit) at week 24 compared with placebo (53.3% and 56.9% vs. 45.5%; odds ratio 1.47 and 1.68; P &lt; 0.05 and P &lt; 0.01, respectively). Donohue et al Respir Med 2013;107:1538-46 Statistically significant improvements in trough FEV1 at day 169 were observed for UMEC/VI 62.5/25 µg, UMEC 62.5 µg and VI 25 µg compared with placebo ([difference; P-value] 0.167 L, 0.115 L, and 0.072 L; all P &lt; 0.001). Statistically significant improvements were also demonstrated for UMEC/ VI 62.5/25 µg compared with UMEC 62.5 µg (0.052 L; P = 0.004) and VI 25 µg at Day 168 (0.095 L; P &lt; 0.001). At days 28, 84, and 168, the odds of being a responder according to TDI focal score (defined as those with an improvement of 1 unit [21]) was higher for UMEC/VI 62.5/25 µg compared with VI 25 µg (odds ratio [OR] at all time points: 1.4; all P &lt; 0.038) and for all active treatments compared with placebo (OR: 1.5-3.1; all P &lt; 0.013). A greater proportion of patients demonstrated a clinically meaningful response in SGRQ score compared with placebo. Improvements were similar across active treatment groups. Trivedi et al Eur Respir J 2014;43:72–81 At day 85, statistically significant (P &lt; 0.001) improvements in least squares mean (LSM) change from baseline in trough FEV1 were observed for UMEC 62.5 μg (127 mL, 95% CI 52–202 mL) and 125 μg (152 mL, 95% CI 76–229 mL) compared with placebo. The UMEC 62.5 and 125 μg treatment groups exhibited an LSM TDI focal score of 0.7 and 1.0 units, respectively, which is approximate to the clinically meaningful improvement of 1 unit, whereas the placebo group had an LSM TDI focal score of -0.3, reflecting a worsening compared to baseline. On day 84, the LSM change from baseline in SGRQ total score was -6.12 (UMEC 125 μg), -3.14 (UMEC 62.5 μg), and +4.75 (placebo). Statistically significant treatment differences (P &lt; 0.001) were observed for both doses (62.5 μg: -7.90 [95% CI -12.20– -3.60]; 125 μg, -10.87 [95% CI -15.25– -6.49]) compared with placebo on day 84. Patients receiving 62.5 μg (OR 2.44, 95% CI 1.08–5.50; p=0.032) or 125 μg (OR 3.20, 95% CI 1.40–7.34; p=0.006) had statistically significantly higher odds of being a SGRQ responder (≥ 4-unit reduction) vs. a nonresponder compared with placebo. Church et al BMC Pulm Med 2014;14:2 Based on the population dose–response model of trough FEV1 data, the geometric mean potency (ED50) of UMEC was 37 μg (95% CI 18-57) with a predicted maximum intrinsic efficacy (Emax) at trough of 0.185 L (95% CI 0.153-0.218) after QD dosing. UMEC 125 μg QD demonstrated the greatest improvements in measure of lung function compared with doses of 62.5 μg and below. UMEC 125 μg QD exhibited more consistent increases in FEV1 from baseline across serial time points over 24 hours compared with other UMEC doses and tiotropium.
- DPI, dry powder inhaler.
- M, minimal clinically important difference; OL, open-label; *, statistically significant; -, not statistically significant; BID, twice daily; QD. once daily. Not all LABA studies shown in table. Placebo groups were allowed to continue their usual respiratory medication, including short-acting bronchodilators as needed, oral and inhaled steroids, and theophylline, but were not allowed other long-acting anticholinergics or long-acting beta agonists. Take-home message: Overall, LABAs shows clinically meaningful improvement measures of lung function, HRQL and dyspnea over placebo. The effects of LABAs on improvement in exercise endurance has been inconsistent (higher dose LABA have shown some improvement in exercise endurance, but not approved dose in Canada) The approved dose of Salmeterol in Canada is 50 mcg bid. Calverley PMA et al. NEJM 2007; 356(8):775-789 Annual rates of exacerbations in the salmeterol group were significantly lower than in the placebo group. Averaged over 3 years, the health status (a reduction of 3.1 units in the score for the St. George’s Respiratory Questionnaire) and spirometric measurements (an increase in FEV1 of 0.092 liter) in the combination-therapy (salmeterol/fluticasone) group were significantly better than in the groups receiving placebo, salmeterol alone, or fluticasone propionate alone. Donohue et al. Chest 2002;122:47-55 At 24 weeks, trough FEV1 had improved significantly above placebo by 137 mL in the tiotropium group and by 85 mL in the salmeterol group. The difference between tiotropium and salmeterol was significant (52 mL, P &lt; 0.01). Dyspnea (TDI): The proportion of patients within each group achieving a 1 U change was 42%, 35%, and 26% for the tiotropium, salmeterol, and placebo groups, respectively. The differences were significant for tiotropium vs. placebo (P 0.01) but not for salmeterol vs. placebo or for tiotropium vs. salmeterol. The proportion of patients within each group achieving a clinically meaningful change (at least 4 U) in the SGRQ total score was 51%, 40%, and 42% for the tiotropium, salmeterol, and placebo groups, respectively. POET-COPD: Vogelmeier et al. N Engl J Med 2011;364:1093-103 Tiotropium, as compared with salmeterol, increased the time to the first exacerbation (187 days vs. 145 days), with a 17% reduction in risk (hazard ratio, 0.83; 95% confidence interval [CI], 0.77 to 0.90; P &lt; 0.001). Tiotropium also increased the time to the first severe exacerbation (hazard ratio, 0.72; 95% CI, 0.61 to 0.85; P &lt; 0.001), reduced the annual number of moderate or severe exacerbations (0.64 vs. 0.72; rate ratio, 0.89; 95% CI, 0.83 to 0.96; P = 0.002), and reduced the annual number of severe exacerbations (0.09 vs. 0.13; rate ratio, 0.73; 95% CI, 0.66 to 0.82; P &lt; 0.001). The approved dose of Formoterol in Canada is 12 mcg bid. Dahl R, et al. Am J Respir Crit Care Med. 2001 Sep 1;164(5):778-84. Formoterol at both 24 mcg and 12 mcg b.i.d. produced statistically and clinically significant improvements in lung function, as measured by FEV1 area under the curve, when compared to placebo after 12 weeks of treatment. The estimated improvement was 208 mL and 200 mL for 24 mcg and 12 mcg b.i.d., respectively. Formoterol was also statistically significant when compared to theophylline. Quality of Life, as measured by the St. George’s Respiratory Questionnaire (SGRQ), was statistically significantly improved in all areas (total, symptoms, activity and impacts) for formoterol (12 mcg b.i.d.) when compared to placebo after 6 months of treatment. Clinically relevant improvement in the symptoms scores were seen in the formoterol 12 mcg b.i.d. treatment group at both 6 and 12 months. Fomoterol at both 24 mcg and 12 mcg b.i.d. produced statistically and clinically significant improvements in lung function, as measured by FEV1 area under the curve, when compared to placebo after 12 weeks of treatment. The estimated improvement was 194 mL and 223 mL for 24 mcg and 12 mcg b.i.d., respectively. Formoterol was also statistically significant when compared to ipratropium bromide. Quality of Life, as measured by the St. George’s Respiratory Questionaire (SGRQ), was both statistically and clinically significantly improved in all areas (total, symptoms, activity and impacts) for formoterol (12 mcg b.i.d.) when compared to placebo with statistically significant improvements for the 24 mcg b.i.d. dose for the total, symptoms and activity scores. The approved dose of Indacaterol in Canada is 75 mcg qd. Study B2354. Reported in Center for Drug Evaluation and Research summary review document for indacaterol. 2011. [Accessed January 4, 2012]. Available from:http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022383Orig1s000TOC.cfm. Study B2355. Reported in Center for Drug Evaluation and Research summary review document for indacaterol. 2011. [Accessed January 4, 2012]. Available from:http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022383Orig1s000TOC.cfm. Results from the two pivotal studies demonstrated that compared to placebo, Onbrez Breezhaler 75 mcg led to a significantly greater trough FEV1 (tFEV1) at 12 weeks by 0.14 L and 0.12 L in study B2355 and B2354, respectively. There was no difference in the rate of change in tFEV1 for indacaterol 75 mcg from Day 29 to Week 12. The key secondary end-point TDI, did not achieve a clinically and statistically significant improvement compared with placebo-treated patients in the B2355 study. However, in the B2354 study both statistically and clinically significant improvements versus placebo were noted. The quality of life questionnaire, SGRQ total score, which was -3.6 in Study B2355 and -3.8 in Study B2354, reached statistical significance versus placebo in both studies; however, it did not meet the predefined clinically meaningful difference of -4. Rescue medication use was also statistically significantly reduced over 12 weeks of treatment with indacaterol 75 mcg compared with placebo.
- AC, adenylyl cyclase; β-arr, β-arrestins; cAMP, cyclic adenosine 3´5´-monophosphate; DAG, diacylglycerol; GRK2, G-protein-coupled-kinase 2; IP3, inositol trisphosphate; PKC, protein kinase C; PLCβ, phospholipase Cβ. Potential cross-talk between β2-adrenoceptors and muscarinic M3 receptors. Activation of the M3 receptor causes activation of PKC, which in turn may lead to phosphorylation of the β2-adrenoceptor, Gsα and GRK2. Phosphorylation of the β2-adrenoceptor and Gsα causes β2-adrenoceptor desensitization by uncoupling the receptor from the effector system. Phosphorylation of GRK2 also leads to the uncoupling of the β2-adrenoceptor through phosphorylation of the cytoplasmic tail of the receptor and subsequent binding of β-arr.
- DPI, dry powder inhaler.
- Tio, tiotropium; UMEC, umeclidinium; VI, vilanterol. M, minimal clinically important difference; *, statistically significant. Take-home message: There are some clinically meaningful improvements for VI/UMEC in lung function over placebo, but not the individual components. Mixed results over tiotropium (one study showed MCID, another did not). There are also no data on VI/UMEC combination therapy on exacerbations or exercise endurance. Placebo groups were allowed to continue their usual respiratory medication, including short-acting bronchodilators as needed, oral and inhaled steroids and theophylline, but were not allowed other long-acting anticholinergics or long-acting beta 2 agonists. Treatment groups were also allowed to continue their usual respiratory medication, including short-acting bronchodilators as needed, oral and inhaled steroids and theophylline. Donohue et al 2013 Statistically significant improvements in trough FEV1 at day 169 were observed for VI/UMEC 25/62.5 µg, UMEC 62.5 µg, and VI 25 µg compared with placebo ([difference; P-value] 0.167 L, 0.115 L, and 0.072 L; all P &lt; 0.001). Statistically significant improvements were also demonstrated for VI/UMEC 25/62.5 µg compared with UMEC 62.5 µg (0.052 L; P = 0.004) and VI 25 µg at day 168 (0.095 L; P &lt; 0.001). At days 28, 84, and 168, the odds of being a responder according to TDI focal score (defined as those with an improvement of 1 unit [21]) was higher for VI/UMEC 25/62.5 µg compared with VI 25 µg (odds ratio [OR] at all time points: 1.4; all P &lt; 0.038) and for all active treatments compared with placebo (OR 1.5-3.1; all P &lt; 0.013). A greater proportion of patients demonstrated a clinically meaningful response in SGRQ score compared with placebo. Improvements were similar across active treatment groups. Maleki-Yazdi et al 2014 A clinically meaningful and statistically significant improvement of 0.112 L (95% confidence interval [CI]: 0.081, 0.144) in trough FEV1 at day 169 was observed for VI/UMEC 25/62.5 µg vs. TIO 18 µg. Statistically significant improvements in St George&apos;s Respiratory Questionnaire (SGRQ) total score were observed for the VI/UMEC 25/62.5 µg group vs. TIO 18 µg at day 28, 84, and 168. SGRQ difference of -2.10 (-3.61, -0.59). Statistically significant but not MID. Decramer et al 2014 In the pooled analysis of trough FEV1 for both studies, we noted an improvement on day 169 for umeclidinium 125 μg plus vilanterol 25 μg compared with tiotropium 18 μg (0.080 L [95% CI 0.044-0.116; P &lt; 0.0001]) and for umeclidinium 62.5 μg plus vilanterol 25 μg compared with tiotropium 18 μg (0.075 L [0.039-0.110; P &lt; 0.0001]). Statistically significant but not MID. The dosage for vilanterol/umeclidinium (25/125 μg) is not approved in Canada.
- MCID, minimal clinically important difference; *, statistically significant; OL, open label Take-home message: There are some clinically meaningful improvements in lung function over placebo and salmeterol-fluticasone. Mixed results over tiotropium (2 studies shown an MCID, 1 study shows only statistical significance). No MCID in lung function over individual components, indacaterol, or glycopyrronium. There are some clinically meaningful improvements in HRQL, dyspnea, and exercise endurance over some comparators, but no difference in exacerbations. Placebo groups were allowed to continue their usual respiratory medication, including short-acting bronchodilators as needed, oral and inhaled steroids, and theophylline, but were not allowed other long-acting anticholinergics or long-acting beta 2 agonists. Treatment groups were also allowed to continue their usual respiratory medication, including short-acting bronchodilators as needed, oral and inhaled steroids, and theophylline. SHINE Bateman et al 2013 Trough FEV1 at week 26 was significantly improved (P &lt; 0.001) with QVA149 compared with indacaterol and glycopyrronium (least squares mean [LSM] differences 0.07 L and 0.09 L, respectively), tiotropium and placebo (LSM differences 0.08 L and 0.20 L, respectively). Only MID vs. placebo. QVA149 was significantly superior to placebo and tiotropium for both the TDI and SGRQ total score at week 26; no other active treatment achieved a significant improvement in SGRQ vs. placebo. Furthermore, a significantly higher proportion of patients on QVA149 achieved a clinically meaningful improvement in TDI (≥ 1 unit) and SGRQ (≥ 4 units) vs. placebo and tiotropium. ILLUMINATE Vogelmeier et al 2012 At week 26, FEV1 AUC 0–12 h was significantly higher with QVA149 than with SFC (treatment difference 0.138 L; 95% CI 0.100-0.176; P &lt; 0.0001). QVA149 significantly increased the transition dyspnea index focal score at week 26 compared with SFC, with a treatment difference of 0.76 (95% CI 0.26-1.26; P = 0.0031). At week 26, 67.5% (143 of 212) of patients receiving QVA149 had a clinically important increase of at least 1 point in index score vs. 56.8% (121 of 213) of patients receiving SFC twice a day (odds ratio 1.56, 95% CI 1.01-2.42; P = 0.046). SPARK Wedzicha et al 2013 QVA149 significantly reduced the rate of moderate to severe exacerbations vs. glycopyrronium by 12% (annualized rate of exacerbations 0.84 [95% CI 0.75-0.94] vs. 0.95 [0.85-1.06]; rate ratio 0.88, 95% CI 0.77-0.99, P = 0.038). Trough FEV1 was significantly higher with QVA149 at all assessments compared with glycopyrronium (differences 70-80 mL; P &lt; 0.0001) and tiotropium (differences 60-80 mL; P &lt; 0.0001). The improvement from baseline in SGRQ total score was 8-9 units with QVA149, 6 units with glycopyrronium, and 5-6 units with tiotropium. The differences in SGRQ total score between QVA149 and glycopyrronium ranged from −1.9 to −2.8 (all P &lt; 0.01), and between QVA149 and tiotropium from −1.7 to −3.1 (all P &lt; 0.05). Percentages of patients achieving the minimum clinically important difference of 4 units in SGRQ total score were significantly higher with QVA149 than with glycopyrronium or tiotropium up to week 52 (at week 64, P = 0.055 and P = 0.051 for QVA149 vs. glycopyrronium and tiotropium, respectively. BRIGHT Beeh et al 2014 At day 21, mean treatment differences in trough IC, FEV1, and FVC were significantly higher for QVA149 vs. placebo (0.19, 0.20 and 0.28 L, respectively) and vs. tiotropium (0.15, 0.10 and 0.11 L, respectively). QVA149 significantly improved exercise endurance time at day 21 compared with placebo (least squares mean treatment difference 60 s [P = 0.006]). No significant improvements in exercise endurance time at day 21 between QVA149 and tiotropium were found. ENLIGHTEN Dahl et al 2013 QVA149 provided a significantly greater and clinically meaningful increase in pre-dose FEV1 from week 3 to week 52 (treatment differences in the range of 0.152-0.189 L; P &lt; 0.001 at all time points vs. placebo.
- MCID, minimal clinically important difference; *, statistically significant; OL, open label Take-home message: There are some statistically significant and clinically meaningful improvements in lung function over monotherapies olodaterol and tiotropium and over placebo. There are some clinically meaningful improvements in HRQL, and dyspnea, with a trend for improvement in exacerbations over monotherapies. Placebo groups were allowed to continue their usual respiratory medication, including short-acting bronchodilators as needed, oral and inhaled steroids, and theophylline, but were not allowed other long-acting anticholinergics or long-acting beta 2 agonists. Treatment groups were also allowed to continue their usual respiratory medication, including short-acting bronchodilators as needed, oral and inhaled steroids, and theophylline. Beeh et al 2015. A significant improvement in FEV1 AUC0-24 response was observed with tiotropium + olodaterol 5/5 μg and 2.5/5 μg versus placebo and monotherapies after 6 weeks of treatment; mean response with tiotropium + olodaterol 5/5 μg versus placebo was 0.280 L (p &lt; 0.0001). Differences to monotherapies with tiotropium + olodaterol 5/5 μg were 0.115 L versus olodaterol 5 μg, 0.127 L versus tiotropium 2.5 μg and 0.110 L versus tiotropium 5 μg (p &lt; 0.0001 for all comparisons). Secondary end points supported these data. No safety concerns were identified. Buhl et al. 2015 In total, 5162 patients (2624 in Study 1237.5 and 2538 in Study 1237.6) received treatment. Both FDCs significantly improved FEV1 AUC0–3 and trough FEV1 response versus the mono-components in both studies. Statistically significant improvements in SGRQ total score versus the mono-components were only seen for tiotropium+olodaterol FDC 5/5 μg. Incidence of adverse events was comparable between the FDCs and the mono-components. Trough FEV1 responses after 24 weeks for tiotropium+olodaterol FDC 2.5/5 μg, 5/5 μg, tiotropium 2.5 μg, 5 μg and olodaterol 5 μg were 111, 136, 83, 65 and 54 mL, respectively, in Study 1237.5, and 125, 145, 62, 96 and 57 mL, respectively, in Study 1237.6. Improvements in the adjusted mean trough FEV1 with tiotropium+olodaterol FDC 5/5 μg and 2.5/5 μg over the corresponding individual components in both the individual studies and the combined data were statistically significant (p&lt;0.05 for all comparisons). Health-related quality of life was measured using St. George’s Respiratory Questionnaire (SGRQ) in the pivotal trials. After 24 weeks, INSPIOLTO RESPIMAT improved mean SGRQ total score compared to tiotropium 5 mcg (-1.23 units, 95%CI -2.31, -0.15) and olodaterol 5 mcg (-1.69 units, 95%CI -2.78, -0.61); improvements were seen in all SGRQ domains. More patients treated with INSPIOLTO RESPIMAT had a clinically meaningful improvement in SGRQ total score (MCID, defined as a decrease of at least 4 units from baseline) compared to tiotropium 5 mcg (57.5% vs. 48.7%) and olodaterol 5 mcg (57.5% vs. 44.8%). After 24 weeks, INSPIOLTO RESPIMAT demonstrated an improvement in reducing shortness of breath, as measured by mean TDI focal score when compared to tiotropium 5 mcg (0.36 units; 95%CI= 0.09 to 0.62) and olodaterol 5 mcg (0.42 units, 95%CI= 0.16 to 0.68). More patients treated with INSPIOLTO RESPIMAT had a clinically meaningful improvement in TDI focal score (MCID, defined as a value of at least 1 unit) compared to tiotropium 5 mcg (54.9% vs. 50.6%) and olodaterol 5 mcg (54.9% vs. 48.2%).
- Buhl et al. 2015 Lung function end points (combined data set) over 52 weeks: full analysis set. a) adjusted mean trough forced expiratory volume in 1 s (FEV1); all comparisons of Tio+Olo 5/5 μg and 2.5/5 μg versus the monotherapies were statistically significant (p&lt;0.05) with the exception of Tio+Olo 2.5/5 μg versus Tio 2.5 μg at day 43. b) FEV1 area under the curve from 0 to 3 h (AUC0–3); all comparisons of Tio+Olo 5/5 μg and 2.5/5 μg versus the monotherapies were statistically significant ( p&lt;0.01). Tio: tiotropium; Olo: olodaterol.
- MCID, minimal clinically important difference; *, statistically significant; OL, open label Take-home message: There are some statistically significant and clinically meaningful improvements in lung function over formoterol and over placebo, but not over aclidinium. There are some clinically meaningful improvements in HRQL and dyspnea over placebo. Placebo groups were allowed to continue their usual respiratory medication, including short-acting bronchodilators as needed, oral and inhaled steroids, and theophylline, but were not allowed other long-acting anticholinergics or long-acting beta 2 agonists. Treatment groups were also allowed to continue their usual respiratory medication, including short-acting bronchodilators as needed, oral and inhaled steroids, and theophylline. AUGMENT: D’Urzo AD et al. 2014. At study end, improvements from baseline in 1-hour postdose FEV1 were significantly greater in patients treated with ACL400/FOR12 FDC or ACL400/FOR6 FDC compared with aclidinium (108 mL and 87 mL, respectively; p &lt; 0.0001). Improvements in trough FEV1 were significantly greater in patients treated with ACL400/FOR12 FDC versus formoterol (45 mL; p = 0.0102), a numerical improvement of 26 mL in trough FEV1 over formoterol was observed with ACL400/FOR6 FDC. Significant improvements in both SGRQ total and TDI focal scores were observed in the ACL400/FOR12 FDC group at study end (p &lt; 0.0001), with differences over placebo exceeding the minimal clinically important difference of ≥4 points and ≥1 unit, respectively. All treatments were well tolerated, with safety profiles of the FDCs similar to those of the monotherapies. ACLIFORM-COPD: Singh D et al. 2014. At Week 24, aclidinium/formoterol 400/12 μg and 400/6 μg lead to significant improvements from baseline in 1-hour post-dose FEV1 versus aclidinium (125 mL [95% CI: 90, 160; p &lt; 0.001] and 69 mL [95% CI: 34, 105; p &lt; 0.001], respectively) and trough FEV1 versus formoterol (85 mL [95% CI: 51, 119; p &lt; 0.001] and 53 mL [95% CI: 19, 87; p &lt; 0.01], respectively; co-primary endpoints). Additionally, aclidinium/formoterol 400/12 μg and 400/6 μg provided significant improvements in Transition Dyspnoea Index (TDI) focal score versus placebo (1.29 units [95% CI: 0.73, 1.86; p &lt; 0.001] and 1.16 units [95% CI: 0.59, 1.73; p &lt; 0.001], respectively; secondary endpoint). All treatments were well tolerated, with safety profiles of the FDCs similar to those of placebo and monotherapy. A significantly higher proportion of patients receiving FDC 400/6 μg had ≥4 units decrease in SGRQ total score at Week 24 versus placebo.
- AUGMENT: D’Urzo AD et al. 2014. Improvements in trough FEV1 were significantly greater in patients treated with ACL400/FOR12 FDC versus formoterol (45 mL; p = 0.0102), a numerical improvement of 26 mL in trough FEV1 over formoterol was observed with ACL400/FOR6 FDC. Mean changes from baseline in morning predose (trough) FEV1 (A) at week 24 (coprimary endpoint). Analyses were based on a mixed-model for repeated measures. *p &lt; 0.05 versus placebo; ‡p &lt; 0.05 versus formoterol and placebo; §p &lt; 0.05 versus aclidinium, formoterol, and placebo. ACL400/FOR12 FDC, fixed-dose combination of aclidinium 400 μg and formoterol 12 μg; ACL400/FOR6 FDC, fixed-dose combination of aclidinium 400 μg and formoterol 6 μg; FEV1, forced expiratory volume in 1 second; LS, least squares.
- Case Recap: Linda is a 71-year-old retired executive assistant who enjoys playing with her grandchildren and gardening, although lately she has had a lot of trouble doing both due to shortness of breath She quit smoking 10 years ago and has a 90 pack-year history She was diagnosed with COPD 8 years ago; she was placed on a tiotropium HandiHaler once daily and salbutamol as needed She recently presented to the emergency department with persistent dyspnea, cough, and purulent sputum She had another exacerbation several years ago FEV1 40% FEV1/FVC 0.59 MRC grade 4
- P = 0.017 between frequent and infrequent exacerbators.
- AECOPD, acute exacerbation of COPD; ICS/LABA, inhaled corticosteroid/LABA (e.g. fluticasone/salmeterol; budesonide/formoterol); LAAC, long-acting anticholinergic (e.g. tiotropium); LABA, long-acting beta 2 agonist (e.g. salmeterol; formoterol); SABA, short-acting beta 2 agonist (e.g. salbutamol; terbutaline); SABD, short-acting bronchodilator (e.g. ipratropium or SABA).
- Recommended and Suggested pharmacological inhaler therapies based on PICO 2: Does maintenance inhaled therapy prevent/decrease acute exacerbations of COPD? according to the CHEST-CTS 2014 guidelines for AECOPD.
- For patients with moderate to severe COPD, who have a history of one or more moderate or severe COPD exacerbations in the previous year despite optimal maintenance inhaler therapy, we suggest the use of a long term macrolide to prevent acute exacerbations of COPD (Grade 2A). Underlying values and preferences: This recommendation places high value on the prevention of COPD exacerbations. However, clinicians prescribing macrolides need to consider in their individual patients the potential for prolongation of the QT interval and hearing loss as well as bacterial resistance. The duration and exact dosage of macrolide therapy is unknown.
- DPI, dry powder inhaler.
- M = minimal clinically important difference; * = statistically significant; - = not statistically significant Key take-home message: Formoterol/budesonide + tiotropium showed clinically meaningful improvement in lung function compared to tiotropium alone. Fluticasone/vilanterol showed clinically meaningful improvement in lung function over fluticasone alone and placebo, but not over vilanterol alone. HRQL was improved, but not reaching MCID for salmeterol/fluticasone and formoterol/budesonide against comparators. Fixed-dose combination therapies showed increased risk of pneumonia. Kardos et al. Am J Resp Crit Care Med 2007;175:144-9 The annualized rate of moderate and severe exacerbations per patient was 0.92 in the combination therapy and 1.4 in the salmeterol group, corresponding to a 35% decrease. In addition, the mean time to first exacerbation in the combination therapy group was significantly longer compared with that of the salmeterol group (128 vs. 93 days, P &lt; 0.0001). Calverley et al. N Engl J Med 2007;356:775-89 Averaged over 3 years, the health status (a reduction of 3.1 units in the score for the St. George’s Respiratory Questionnaire) and spirometric measurements (an increase in FEV1 of 0.092 L) in the combination-therapy group were significantly better than in the groups receiving placebo, salmeterol alone, or fluticasone propionate alone. Statistically significant but not MCID. Compared with placebo, the combination regimen reduced the annual rate of exacerbations from 1.13 to 0.85. Wedzicha et al. Am J Resp Crit Care Med 2007;177:19-26 The SGRQ total score was statistically significantly lower at 2 years on salmeterol/fluticasone propionate vs. tiotropium (difference 2.1 units; 95% CI, 0.1-4.0; P = 0.038). Statistically significant but not MCID. Welte et al. Am J Resp Crit Care Med 2009;180:741-50 Budesonide/formoterol added to tiotropium also increased post-dose FEV1 vs. tiotropium alone by 123 and 131 mL at 5 and 60 minutes post-dose, respectively. Over the study period, SGRQ-C total score improved by 3.8 units with budesonide/formoterol added to tiotropium compared with 1.5 units with tiotropium alone (mean difference, –2.3; 95% CI: –4.23, –0.32; P = 0.023). Improvements in SGRQ-C total score by more than 4 units were seen in 49.5% and 40.0% of patients in the budesonide/formoterol added to tiotropium and tiotropium alone arms, respectively (P = 0.016); a similar proportion of patients in each arm had a deterioration in SGRQ-C total score by more than 4 units (27.6% and 29.7%, respectively). Sharafkhaneh et al. Respir Med 2012;106:257-68 Compared with formoterol, treatment with budesonide/formoterol 320/9 μg and 160/9 μg resulted in reductions in the COPD exacerbation rate of 34.8% and 25.9%, respectively, for those requiring oral corticosteroids and of 26.8% and 12.2%, respectively, for those requiring hospitalization. Mean changes from baseline to the end of treatment in SGRQ total score met the MCID for a clinically meaningful improvement with all 3 treatments; however, differences between treatment groups were not statistically significant. Kerwin et al. Respir Med 2013;107:560-9 The combination of FF/VI at a strength of 100/25 μg significantly (P &lt; 0.001) improved trough FEV1 (115 mL) vs. placebo. Similar effects were observed with FF/VI 50/25 μg; no significant difference was seen between FF/VI 100/25 μg and VI 25 μg for trough FEV1 (48 mL, P = 0.082); VI 25 μg over 24 weeks improved lung function vs. placebo significantly for trough FEV1 (67 mL, P = 0.017). Martinez et al. Respir Med 2013;107:550-9 There was a statistically significant (P &lt; 0.001) increase in wm FEV1 (209 mL) and trough FEV1 (131 mL) for FF/VI 200/25 μg vs. placebo; similar changes were seen for FF/VI 100/25 μg vs. placebo. Whereas the difference between FF/VI 200/25 μg and VI 25 μg in change from baseline trough FEV1 (32 mL) was not statistically significant (P = 0.224), the difference between FF/VI 200/25 μg and FF 200 μg for wm FEV1 (168 mL) was significantly different (P &lt; 0.001). VI 25 μg significantly improved wm and trough FEV1 vs. placebo (209 mL and 131 mL, respectively). Dransfield et al. Lancet Respir Med 2013;1:210-3 In the pooled analysis, significantly fewer moderate and severe exacerbations were noted in all fluticasone furoate/vilanterol groups than in the vilanterol only group (P = 0.0141 for the 50 μg group, &lt;0.0001 for the 100 μg group, and 0.0003 for the 200 μg group).
- A 6-week, multicentre, randomized, double-blind, parallel-group study was conducted in patients with COPD to compare lung function improvements of tiotropium 18 g qd plus formoterol 12 g bid to salmeterol 50 g bid plus fluticasone 500 g bid. Methods: Following a screening visit, subjects entered a run-in period in which they received regular ipratropium. At randomization, patients were assigned to either tiotropium plus formoterol or salmeterol plus fluticasone. After 6 weeks of treatment, a 12-h lung function profile was obtained. The coprimary endpoints were FEV1 area under the curve for the time period 0 to 12 h (AUC0–12h) and peak FEV1. 592 patients were included in the study.
- MCID, minimal clinically important difference; SFC, salmeterol/ fluticasone. MCID in health status is 4 units. The SGRQ total score was statistically significantly lower at 2 years on salmeterol/fluticasone propionate vs. tiotropium (difference 2.1 units; 95% CI, 0.1-4.0; P = 0.038). Statistically significant but not MCID. Methods: A total of 1,323 patients (mean age 64 years, post-bronchodilator FEV1, 39% predicted) were randomized in this 2-year, double-blind, double-dummy parallel study. Measurements and Main Results: Primary endpoint was health care utilization exacerbation rate. Other endpoints included health status measured by St. George’s Respiratory Questionnaire, mortality, adverse events, and study withdrawal. Probability of withdrawing from the study was 29% greater with tiotropium than salmeterol/fluticasone propionate (P = 0.005). The modelled annual exacerbation rate was 1.28 in the salmeterol/fluticasone propionate group and 1.32 in the tiotropium group (rate ratio, 0.967; 95% CI, 0.836–1.119]; P = 0.656). The SGRQ total score was statistically significantly lower at 2 years on salmeterol/fluticasone propionate vs. tiotropium (difference 2.1 units; 95% CI, 0.1–4.0; P = 0.038). Mortality was significantly lower in the salmeterol/fluticasone propionate group; 21 (3%) of patients in this group died compared with 38 (6%) in the tiotropium group (P = 0.032). More pneumonias were reported in the salmeterol/fluticasone propionate group relative to tiotropium (P = 0.008).
- SFC, salmeterol/fluticasone. Wedzicha JA, Calverley PMA, Seemungal TA, et al, for the INSPIRE Investigators. The prevention of COPD exacerbations by salmeterol/fluticasone propionate or tiotropium bromide. Am J Respir Crit Care Med 2008;177:19-26.
- WISDOM study: In this 12-month, double-blind, parallel-group study, 2,485 patients with a history of exacerbation of COPD received triple therapy consisting of tiotropium (at a dose of 18 μg once daily), salmeterol (50 μg twice daily), and the inhaled glucocorticoid fluticasone propionate (500 μg twice daily) during a 6-week run-in period. Patients were then randomly assigned to continued triple therapy or withdrawal of fluticasone in three steps over a 12-week period. The primary endpoint was the time to the first moderate or severe COPD exacerbation. Spirometric findings, health status, and dyspnea were also monitored.
- WISDOM study: In this 12-month, double-blind, parallel-group study, 2,485 patients with a history of exacerbation of COPD received triple therapy consisting of tiotropium (at a dose of 18 μg once daily), salmeterol (50 μg twice daily), and the inhaled glucocorticoid fluticasone propionate (500 μg twice daily) during a 6-week run-in period. Patients were then randomly assigned to continued triple therapy or withdrawal of fluticasone in three steps over a 12-week period. The primary endpoint was the time to the first moderate or severe COPD exacerbation. Spirometric findings, health status, and dyspnea were also monitored. MCID for lung function is 100-140 mL.
- BUD/FORM, budesonide/formoterol; PBO, placebo; TIO, tiotropium. Mean number of severe exacerbations per patient vs. time. Circles represent BUD/FORM + TIO; squares represent PBO + TIO. Poisson regression: rate ratio, 0.38 (95% CI, 0.25–0.57; P &lt; 0.001). Total number of events: BUD/FORM + TIO (n = 329), 31; PBO 1 TIO (n = 330), 82. Patients with one or more severe exacerbations: BUD/FORM + TIO (n = 329), 25; PBO + TIO (n = 330).
- CI, confidence interval; FEV1, forced expiratory volume in 1 second; FF, fluticasone furoate; LS, least squares; MCID, minimal clinically important difference; VI = vilanterol. MCID for lung function is 100-140 mL. Least squares mean trough FEV1, change from baseline from day 2 to day 169. The combination of FF/VI at a strength of 100/25 μg significantly (P &lt; 0.001) improved trough FEV1 (115 mL) vs. placebo. Similar effects were observed with FF/VI 50/25 μg; no significant difference was seen between FF/VI 100/25 μg and VI 25 μg for trough FEV1 (48 mL, P = 0.082); VI 25 μg over 24 weeks improved lung function vs. placebo significantly for trough FEV1 (67 mL, P = 0.017).
- M, minimal clinically important difference; SAE, serious adverse event, *, statistically significant; ↑, improvement; ↓, decrease. LABA/tiotropium vs. tiotropium shows MCID in lung function and dyspnea, but not in health status or exacerbations. ICS/LABA vs. tiotropium does not result in MCID for any health outcome. ICS/LABA + tiotropium vs. tiotropium shows MCID for lung function and health status, but not in dyspnea or exacerbations. Systematic review of 23 trials (6,803 participants) were included. “Dual” therapy showed significant improvements in forced volume in the first second (FEV1), health-related quality of life (HRQL), and dyspnea. However, it failed to reduce the risk of COPD exacerbations. Compared with tiotropium, “combined” therapy presented modest but significant effects on FEV1, HRQL, and dyspnea. Again, there was no significant difference in exacerbations, but it was associated with a significant increase of serious adverse events (number need to treat for harm ¼ 20; 95% CI: 11-119). Finally, “triple therapy” increased FEV1, improved HRQL (both benefits exceeded minimal important differences) and decreased COPD exacerbations in a nonsignificant way (odds ratio 0.57; 95% CI 0.24-1.37; P = 0.21). Trials compared here enrolled patients with stable COPD that met moderate to very severe GOLD criteria (average FEV1 of 41% predicted).
- Treatment Evolution after COPD Diagnosis in the UK Primary Care Setting A total of 3,199 patients with at least one prescription of a maintenance therapy at baseline and during 4th-6th month interval were included in the analysis. At diagnosis (0–3 months), the most frequently prescribed maintenance therapy was LABA + ICS (43%), followed by LAMA (24%) and LABA + LAMA + ICS (23%). Nearly half the patients (LABA 50%, LAMA 43%) starting on a monobronchodilator had additions to their treatment in 24 months. Compared to other medications, patients starting on a LAMA were most likely to escalate to triple therapy in 24 months. Nearly one-fourth of the patients prescribed triple therapy at baseline stepped down to LABA+ ICS (25%) or LAMA (31%) within 24 months. Severity of COPD GOLD 1 448 (14.00%) GOLD2 1,557 (48.67%) GOLD 3925 (28.92%) GOLD4185 (5.78%)
- Wisdom study notes discuss withdrawal approach in this study.
- A1. Consider the role of macrolide or PDE4 inhibitor. A2. Consider optimizing current therapy and then add on narcotics. Look for cardiac disease if symptoms persist. Consider associated sleep apnea -- ask about excessive daytime somnolence. Consider the role of the STOP-BANG questionnaire.
- LABA, long-acting beta 2 agonist; ICS, inhaled corticosteroid; LAMA, long-acting muscarinic antagonist; PDE4inh; phosphodiesterase-4 inhibitor; SABA, short-acting beta 2 agonist; SAMA, short-acting muscarinic antagonist. Medications in each box are alphabetical order -- not necessarily in order of preference. Other possible treatments: Medications in this column can be used alone or in combination with other options.
- ICS/LABA, inhaled corticosteroid/LABA (e.g. fluticasone/salmeterol; budesonide/formoterol); LABA, long-acting beta 2 agonist (e.g. salmeterol; formoterol); LAMA, long-acting muscarinic antagonist (e.g. tiotropium); SABA, short-acting beta 2 agonist (e.g. salbutamol; terbutaline); SABD, short-acting bronchodilator (e.g. ipratropium or SABA). Lower-dose ICS/LABA refers to Advair 250/50 µg twice daily.